Volatile Organic Compounds in Cellular Headspace after Hyperbaric Oxygen Exposure: An In Vitro Pilot Study.

Volatile organic compounds (VOCs) might be associated with pulmonary oxygen toxicity (POT). This pilot study aims to identify VOCs linked to oxidative stress employing an in vitro model of alveolar basal epithelial cells exposed to hyperbaric and hyperoxic conditions. In addition, the feasibility of this in vitro model for POT biomarker research was evaluated. The hyperbaric exposure protocol, similar to the U.S. Navy Treatment Table 6, was conducted on human alveolar basal epithelial cells, and the headspace VOCs were analyzed using gas chromatography-mass spectrometry. Three compounds (nonane [p = 0.005], octanal [p = 0.009], and decane [p = 0.018]), of which nonane and decane were also identified in a previous in vivo study with similar hyperbaric exposure, varied significantly between the intervention group which was exposed to 100% oxygen and the control group which was exposed to compressed air. VOC signal intensities were lower in the intervention group, but cellular stress markers (IL8 and LDH) confirmed increased stress and injury in the intervention group. Despite the observed reductions in compound expression, the model holds promise for POT biomarker exploration, emphasizing the need for further investigation into the complex relationship between VOCs and oxidative stress.

Chain of events analysis in diving accidents treated by the Royal Netherlands Navy 1966-2023.

Introduction: Diving injuries are influenced by a multitude of factors. Literature analysing the full chain of events in diving accidents influencing the occurrence of diving injuries is limited. A previously published 'chain of events analysis' (CEA) framework consists of five steps that may sequentially lead to a diving fatality. This study applied four of these steps to predominately non-lethal diving injuries and aims to determine the causes of diving injuries sustained by divers treated by the Diving Medical Centre of the Royal Netherlands Navy. Methods: This retrospective cohort study was performed on diving injuries treated by the Diving Medical Centre between 1966 and 2023. Baseline characteristics and information pertinent to all four steps of the reduced CEA model were extracted and recorded in a database. Results: A total of 288 cases met the inclusion criteria. In 111 cases, all four steps of the CEA model could be applied. Predisposing factors were identified in 261 (90%) cases, triggers in 142 (49%), disabling agents in 195 (68%), and 228 (79%) contained a (possible-) disabling condition. The sustained diving injury led to a fatality in seven cases (2%). The most frequent predisposing factor was health conditions (58%). Exertion (19%), primary diver errors (18%), and faulty equipment (17%) were the most frequently identified triggers. The ascent was the most frequent disabling agent (52%). Conclusions: The CEA framework was found to be a valuable tool in this analysis. Health factors present before diving were identified as the most frequent predisposing factors. Arterial gas emboli were the most lethal injury mechanism.

An observational study ascertaining the prevalence of bullae and blebs in young, healthy adults and its possible implications for scuba diving.

Introduction: Intrapulmonary air-filled cavities, e.g., bullae, blebs, and cysts, are believed to contribute topulmonary barotrauma (PBT) and arterial gas embolism (AGE) in divers. However, literature is unclear about the prevalence of bullae in healthy adults, ranging from 2.3-33.8%. While this could in part be explained due to increasing quality of radiologic imaging, such as computed tomography (CT) scans, other methodological factors may also affect these findings. This study aims to ascertain the prevalence of bullae in young and healthy adults. Methods: This single-center cross-sectional observational study re-assessed the CT scans of adults (aged 18-40) performed for a clinical suspicion for pulmonary embolism, from 1 January 2016 to 1 March 2020. Presence of bullae was recorded in an electronic database. Chi-square and Fisher exact tests were used for statistical analyses. Additionally, a multivariate logistic regression analysis was performed to study the independent predictive value of identified risk factors. Results: A total of 1,014 cases were identified, of which 836 could be included. Distribution amongst age groups (18-25, 26-30, 31-35, and 36-40) was almost equally, however, 75% of the population was female. Of the male proportion, 41% smoked, compared to 27% in females. In 7.2% (95% CI 5.6-9.1) bullae were identified. The prevalence increased with increasing age (p < 0.001), with odd ratios up to 5.347 (95% CI 2.164-13.213, p < 0.001) in the oldest age group. Males and smokers had higher odds ratios for bullae of 2.460 (95% CI 1.144-4.208; p = 0.001) and 3.406 (95% CI 1.878-6.157, p < 0.001), respectively. Similar results were seen in the multivariate logistic regression analysis, where age, male sex and smoking were all statistically significant independent risk factors for bullae. Discussion: Bullae were seen in 7.2% of a healthy population up to 40 years old. Increasing age, smoking, and being male were identified as statistically significant risk factors, both in independent and in multivariate logistic regression analyses. Our observations may warrant a re-evaluation of the contribution of bullae to PBT and AGE, as the latter two occur very rarely and bullae appear to be more frequently present than earlier assumed.

Pulmonary oxygen toxicity breath markers after heliox diving to 81 metres.

Pulmonary oxygen toxicity (POT), an adverse reaction to an elevated partial pressure of oxygen in the lungs, can develop as a result of prolonged hyperbaric hyperoxic conditions. Initially starting with tracheal discomfort, it results in pulmonary symptoms and ultimately lung fibrosis. Previous studies identified several volatile organic compounds (VOCs) in exhaled breath indicative of POT after various wet and dry hyperbaric hypoxic exposures, predominantly in laboratory settings. This study examined VOCs after exposures to 81 metres of seawater by three navy divers during operational heliox diving. Univariate testing did not yield significant results. However, targeted multivariate analysis of POT-associated VOCs identified significant (P = 0.004) changes of dodecane, tetradecane, octane, methylcyclohexane, and butyl acetate during the 4 h post-dive sampling period. No airway symptoms or discomfort were reported. This study demonstrates that breath sampling can be performed in the field, and VOCs indicative of oxygen toxicity are exhaled without clinical symptoms of POT, strengthening the belief that POT develops on a subclinical-to-symptomatic spectrum. However, this study was performed during an actual diving operation and therefore various confounders were introduced, which were excluded in previous laboratory studies. Future studies could focus on optimising sampling protocols for field use to ensure uniformity and reproducibility, and on establishing dose-response relationships.

Current Perspectives on the Management of Patients Poisoned With Novichok: A Scoping Review.

INTRODUCTION: Nerve agents have emerged as a global threat since their discovery in the 1930s, posing severe risks due to their inhibition of acetylcholinesterase and the subsequent accumulation of acetylcholine in nerve synapses. Despite the enforcement of the Chemical Weapon Convention to control chemical weapons, including nerve agents, recent events, such as the Novichok attacks on Sergei Skripal and Alexei Navalny, have highlighted the persistent threat. Novichok, a distinct class of nerve agents, raises specific concerns regarding its management due to limited understanding. This article aims to comprehensively analyze existing literature. MATERIALS AND METHODS: A scoping review was employed to comprehensively assess the current state of knowledge on managing patients poisoned with Novichok. Following the PRISMA-ScR guidelines, relevant literature was identified in peer-reviewed journals covering symptoms, diagnosis, treatment, decontamination, and long-term effects. Searches were conducted on February 1, 2023, across four electronic databases (PubMed, EMBASE, MEDLINE, and Web of Science) using "Novichok" as a keyword. No restrictions were applied, and additional studies were sought from the references of identified papers. Eligible papers included discussions on Novichok or its specific properties impacting management, regardless of study type, language, or publication date, while those unrelated to the study's conceptual framework were excluded. RESULTS: A total of 170 records were identified from the initial database search, with 86 studies screened after removing duplicates. Among these, 28 publications met the eligibility criteria and were included in the analysis. An additional relevant study was identified from the citation lists of included studies, bringing the total to 29. The review encompasses studies published from 2018 onwards, indicating the growing interest in this topic. While most studies are reviews on Novichok or nerve agents in general, several theoretical and experimental investigations were also found. CONCLUSION: This review highlights the significant uncertainties and knowledge gaps surrounding the management of patients poisoned with Novichok. While some aspects align with other nerve agents, limited research likely due to safety and ethical challenges leads to assumptions and uncertainties in patient care. The review identifies areas with ongoing research, such as decontamination and biomarker recognition, while other aspects remain understudied. The possible inefficacy of current treatment options and the need for further research on oximes, bioscavengers, and long-term effects emphasize the necessity for increased research to optimize patient outcomes. More studies are essential to clarify the actual threat and toxicity of Novichok. Moreover, raising awareness among medical staff is crucial for early diagnosis, prompt treatment, and safety. This review offers valuable insights into managing Novichok-poisoned patients and calls for increased research and awareness in this critical area.

Self-reported vitality and health status are higher in Dutch submariners than in the general population.

Introduction: Living aboard submarines has a potential negative effect on health. Although studies have evaluated specific health hazards and short-term outcomes, long-term health effects have not been investigated in this population. Methods: Veteran submariners were contacted through the veterans' society and administered a World Health Organisation validated questionnaire (SF-36) assessing their physical, emotional, and social functioning. Scores were compared with those of the general (reference) population and scores in veteran submariners were differentiated by rank, time at sea and time in service. Statistical analyses were performed using the Wilcoxon signed rank and Kruskal-Wallis tests. Results: Of the 1,025 submariners approached in December 2019, 742 (72.4%) completed and returned the questionnaire before July 2020. All 742 were men, of median age 68 (interquartile range [IQR] 59-76) years (range 34-99 years). Of these subjects, 10.3% were current smokers, 64.4% were former smokers and 23.7% had never smoked. Submariners scored significantly better (P < 0.001) than the general population on all eight domains of the SF-36. Except for 'pain' and 'change in health status over the last year', scores for all domains decreased with age. Scores were not significantly affected by smoking status, rank, service, and time at sea. Conclusions: Dutch veteran submariners have better self-reported vitality and health status than the general Dutch population. Rank, service, and time at sea did not significantly affect scores of Dutch submariners.

Diving with psychotropic medication: review of the literature and clinical considerations.

This review discusses the safety concerns associated with diving while using psychotropic medication and the limited literature available on the topic. Despite the risks, some divers continue to dive while taking these medications, and their reasons for doing so are unclear. The exact mechanisms of action of these drugs in hyperbaric environments are poorly understood. While current standards and advice for fitness-to-dive assessments are based on limited evidence and expert opinion, developing evidence-based strategies could improve patient care and optimise diving safety. This review appraises relevant literature in diving medicine and provides clinical perspectives for diving physicians conducting fitness-to-dive assessments on patients using psychotropic medication.

Daily Caffeine Intake and the Effect of Caffeine on Pilots' Performance After Extended Wakefulness.

INTRODUCTION: Fatigue is a major contributor to aviation accidents. Sufficient sleep may be difficult to achieve under operational conditions in military aviation. Countermeasures include caffeine, however, studies evaluating its effects often do not represent daily practice with regular caffeine consumption. This study aims to establish the effect of caffeine on psychomotor performance in a realistic scenario (i.e., after a limited period of extended wakefulness).METHODS: This randomized, double-blind, crossover, placebo-controlled trial included 30 aeromedically fit subjects. On trial days, subjects followed their normal routine till 17:00, after which caffeine intake was stopped. At midnight, subjects were given 300 mg of caffeine or placebo and performed the Psychomotor Vigilance Test, Vigilance and Tracking Test, and the Stanford Sleepiness Scale hourly up to 04:00 and again at 06:00 and 08:00. Four blood samples were collected. Statistical analyses included repeated-measures ANOVA or Friedman tests, marginal models, and Wilcoxon Signed Rank tests.RESULTS: Median time awake at midnight was 17 h (IQR 16.5-17.5 h). Performance decreased significantly less during the night in the caffeine condition versus placebo. Neither habitual intake nor daytime caffeine consumption affected this. No statistically significant correlation was identified between blood concentrations of caffeine and performance.DISCUSSION: A single dose of 300 mg of caffeine has beneficial effects on performance during the night in a realistic scenario for military aviation. Daytime caffeine consumption does not affect the effects of caffeine at night. These findings could be relevant for all industries in which optimal performance is required during nighttime after a limited period of extended wakefulness.Wingelaar-Jagt YQ, Wingelaar TT, de Vrijer L, Riedel WJ, Ramaekers JG. Daily caffeine intake and the effect of caffeine on pilots' performance after extended wakefulness. Aerosp Med Hum Perform. 2023; 94(10):750-760.

Analysis of Volatile Organic Compounds in Exhaled Breath Following a COMEX-30 Treatment Table.

The COMEX-30 hyperbaric treatment table is used to manage decompression sickness in divers but may result in pulmonary oxygen toxicity (POT). Volatile organic compounds (VOCs) in exhaled breath are early markers of hyperoxic stress that may be linked to POT. The present study assessed whether VOCs following COMEX-30 treatment are early markers of hyperoxic stress and/or POT in ten healthy, nonsmoking volunteers. Because more oxygen is inhaled during COMEX-30 treatment than with other treatment tables, this study hypothesized that VOCs exhaled following COMEX-30 treatment are indicators of POT. Breath samples were collected before and 0.5, 2, and 4 h after COMEX-30 treatment. All subjects were followed-up for signs of POT or other symptoms. Nine compounds were identified, with four (nonanal, decanal, ethyl acetate, and tridecane) increasing 33-500% in intensity from before to after COMEX-30 treatment. Seven subjects reported pulmonary symptoms, five reported out-of-proportion tiredness and transient ear fullness, and four had signs of mild dehydration. All VOCs identified following COMEX-30 treatment have been associated with inflammatory responses or pulmonary diseases, such as asthma or lung cancer. Because most subjects reported transient pulmonary symptoms reflecting early-stage POT, the identified VOCs are likely markers of POT, not just hyperbaric hyperoxic exposure.

Comparison of effects of modafinil and caffeine on fatigue-vulnerable and fatigue-resistant aircrew after a limited period of sleep deprivation.

Introduction: Literature suggests pilots experience fatigue differently. So-called fatigue-resistant or -vulnerable individuals might also respond differently to countermeasures or stimulants. This study, which is part of a larger randomized controlled clinical trial, aims to investigate the effect of caffeine and modafinil on fatigue-resistant and -vulnerable pilots. Methods: This study included 32 healthy employees of the Royal Netherlands Air Force, who completed three test days, separated by at least 7 days. After a regular work day, the subjects were randomly administered either 300 mg caffeine, 200 mg modafinil or placebo at midnight. Hereafter the subjects performed the psychomotor vigilance test (PVT), vigilance and tracking test (VigTrack) and Stanford sleepiness scale (SSS) six times until 8 a.m. the next day. Subjects were ranked on the average number of lapses on the PVT during the placebo night and divided into three groups: fatigue-vulnerable (FVUL), -intermediate (FINT) and -resistant (FRES), with 11, 10 and 11 subjects in each group, respectively. Area under the curve (AUC) of the PVT, VigTrack and SSS during the test nights were calculated, which were used in univariate factorial analysis of variance (ANOVA). Tukey's HSD post hoc tests were used to differentiate between the groups. Results: A significant effect of treatment was found in the ANOVA of both PVT parameters, VigTrack mean reaction time and SSS. There was a statistically significant effect of fatigue group on all PVT parameters and VigTrack mean percentage omissions, where FINT and FRES scored better than FVUL. There was a significant interaction effect between treatment and fatigue group for PVT number of lapses. This is congruent for the AUC analyses in which for all parameters (except for the SSS) the performance of the FVUL group was consistently worse than that of the FINT and FRES groups. Discussion: This study demonstrates that the performance of individuals with different fatigue tolerances are differently affected by simulants after a limited period of sleep deprivation. The classification of fatigue tolerance through PVT lapses when sleep deprived seems to be able to predict this.

Pulmonary Oxygen Toxicity Through Exhaled Breath Markers After Hyperbaric Oxygen Treatment Table 6.

Introduction: The hyperbaric oxygen treatment table 6 (TT6) is widely used to manage dysbaric illnesses in divers and iatrogenic gas emboli in patients after surgery and other interventional procedures. These treatment tables can have adverse effects, such as pulmonary oxygen toxicity (POT). It is caused by reactive oxygen species' damaging effect in lung tissue and is often experienced after multiple days of therapy. The subclinical pulmonary effects have not been determined. The primary aim of this study was to measure volatile organic compounds (VOCs) in breath, indicative of subclinical POT after a TT6. Since the exposure would be limited, the secondary aim of this study was to determine whether these VOCs decreased to baseline levels within a few hours. Methods: Fourteen healthy, non-smoking volunteers from the Royal Netherlands Navy underwent a TT6 at the Amsterdam University Medical Center-location AMC. Breath samples for GC-MS analysis were collected before the TT6 and 30 min, 2 and 4 h after finishing. The concentrations of ions before and after exposure were compared by Wilcoxon signed-rank tests. The VOCs were identified by comparing the chromatograms with the NIST library. Compound intensities over time were tested using Friedman tests, with Wilcoxon signed-rank tests and Bonferroni corrections used for post hoc analyses. Results: Univariate analyses identified 11 compounds. Five compounds, isoprene, decane, nonane, nonanal and dodecane, showed significant changes after the Friedman test. Isoprene demonstrated a significant increase at 30 min after exposure and a subsequent decrease at 2 h. Other compounds remained constant, but declined significantly 4 h after exposure. Discussion and Conclusion: The identified VOCs consisted mainly of (methyl) alkanes, which may be generated by peroxidation of cell membranes. Other compounds may be linked to inflammatory processes, oxidative stress responses or cellular metabolism. The hypothesis, that exhaled VOCs would increase after hyperbaric exposure as an indicator of subclinical POT, was not fulfilled, except for isoprene. Hence, no evident signs of POT or subclinical pulmonary damage were detected after a TT6. Further studies on individuals recently exposed to pulmonary irritants, such as divers and individuals exposed to other hyperbaric treatment regimens, are needed.

Volatile Organic Compounds Frequently Identified after Hyperbaric Hyperoxic Exposure: The VAPOR Library.

Diving or hyperbaric oxygen therapy with increased partial pressures of oxygen (pO2) can have adverse effects such as central nervous system oxygen toxicity or pulmonary oxygen toxicity (POT). Prevention of POT has been a topic of interest for several decades. One of the most promising techniques to determine early signs of POT is the analysis of volatile organic compounds (VOCs) in exhaled breath. We reanalyzed the data of five studies to compose a library of potential exhaled markers for the early detection of POT. GC-MS data from five hyperbaric hyperoxic studies were collected. Wilcoxon signed-rank tests were used to compare baseline- and postexposure measurements; all ion fragments that significantly varied were compared by similarity using the National Institute of Standards and Technology (NIST) library. All identified molecules were cross-referenced with open-source databases and other scientific publications on VOCs to exclude compounds that occurred as a result of contamination, and to identify the compounds most likely to occur due to hyperbaric hyperoxic exposure. After identification and removal of contaminants, 29 compounds were included in the library. This library of hyperbaric hyperoxic-related VOCs can help to advance the development of an early noninvasive marker of POT. It enables validation by others who use more targeted MS-related techniques, instead of full-scale GC-MS, for their exhaled VOC research.

The lower limit for FEV1/FVC in dive medical assessments: a retrospective study.

INTRODUCTION: Interpreting pulmonary function test (PFT) results requires a valid reference set and a cut-off differentiating pathological from physiological pulmonary function; the lower limit of normal (LLN). However, in diving medicine it is unclear whether an LLN of 2.5% (LLN-2.5) or 5% (LLN-5) in healthy subjects constitutes an appropriate cut-off. METHODS: All PFTs performed at the Royal Netherlands Navy Diving Medical Centre between 1 January 2015 and 1 January 2021 resulting in a forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and/or FEV1/FVC with a Z-score between -1.64 (LLN-5) and -1.96 (LLN-2.5) were included. Records were screened for additional tests, referral to a pulmonary specialist, results of radiological imaging, and fitness to dive. RESULTS: Analysis of 2,108 assessments in 814 subjects showed that 83 subjects, 74 men and nine women, mean age 32.4 (SD 8.2) years and height 182 (7.0) cm, had an FVC, FEV1 and/or FEV1/FVC with Z-scores between -1.64 and -1.96. Of these 83 subjects, 35 (42%) underwent additional tests, 77 (93%) were referred to a pulmonary specialist and 31 (37%) underwent high-resolution CT-imaging. Ten subjects (12%) were declared 'unfit to dive' for various reasons. Information from their medical history could have identified these individuals. CONCLUSIONS: Use of LLN-2.5 rather than LLN-5 for FEV1/FVC in asymptomatic individuals reduces additional investigations and referrals to a pulmonary specialist without missing important diagnoses, provided a thorough medical history is taken. Adoption of LLN-2.5 could save resources spent on diving medical assessments and protect subjects from harmful side effects associated with additional investigations, while maintaining an equal level of safety.

Fatigue in Aviation: Safety Risks, Preventive Strategies and Pharmacological Interventions.

Fatigue poses an important safety risk to civil and military aviation. In addition to decreasing performance in-flight (chronic) fatigue has negative long-term health effects. Possible causes of fatigue include sleep loss, extended time awake, circadian phase irregularities and work load. Despite regulations limiting flight time and enabling optimal rostering, fatigue cannot be prevented completely. Especially in military operations, where limits may be extended due to operational necessities, it is impossible to rely solely on regulations to prevent fatigue. Fatigue management, consisting of preventive strategies and operational countermeasures, such as pre-flight naps and pharmaceuticals that either promote adequate sleep (hypnotics or chronobiotics) or enhance performance (stimulants), may be required to mitigate fatigue in challenging (military) aviation operations. This review describes the pathophysiology, epidemiology and effects of fatigue and its impact on aviation, as well as several aspects of fatigue management and recommendations for future research in this field.