Brain Magnetic Resonance Imaging Responses to Nonhypoxic Hypobaric Decompression.

INTRODUCTION: The pathophysiological basis of neurological decompression sickness and the association between cerebral subcortical white matter (WM) change and nonhypoxic hypobaria remain poorly understood. Recent study of altitude decompression sickness risk evaluated acute WM responses to intensive hypobaric exposure using brain magnetic resonance imaging. METHODS: Six healthy men (20 to 50 yr) completed 6 h of hyperoxic hypobaria during three same-day altitude chamber decompressions to pressure altitudes ≥ 22,000 ft (6706 m). Research magnetic resonance imaging sequences, conducted on the days preceding and following decompression, evaluated subcortical WM integrity, cerebral blood flow, neuronal integrity (fractional anisotropy), and neurometabolite concentrations. RESULTS: No subcortical lesions were evident on diffusion weighted imaging and WM fractional anisotropy was unaffected. Mean WM blood flow was upregulated by 20% to over 25 mL · 100 g-1 · min-1. Gray matter flow was unchanged. There were no changes in gray matter or cerebellar neurometabolites. In parietal subcortical WM, levels of γ-aminobutyric acid (GABA) fell from (mean ± SD) 1.68 ± 0.2 to 1.35 ± 0.3 institutional units while glutathione (GSH) fell from 1.71 ± 0.4 to 1.25 ± 0.3 institutional units. Lactate increased postexposure in five subjects. CONCLUSIONS: Postexposure decrements in GABA and GSH imply WM insult with loss of neuroprotection and oxidative stress. An association between decrements in GABA and GSH support a common origin, while GSH decrements also correlate with WM blood flow responses. WM lactate increments are prone to error but suggest dysregulation of subcortical microvascular flow. WM neurometabolite and blood flow indices did not normalize by 24 h postexposure. Connolly D, Davagnanam I, Wylezinska-Arridge M, Mallon D, Wastling S, Lee VM. Brain magnetic resonance imaging responses to nonhypoxic hypobaric decompression. Aerosp Med Hum Perform. 2024; 95(10):733-740.

Brain and Lung Biomarker Responses to Hyperoxic Hypobaric Decompression.

INTRODUCTION: Biomarker responses to intensive decompression indicate systemic proinflammatory responses and possible neurological stress. To further investigate responses, 12 additional brain and lung biomarkers were assayed.METHODS: A total of 15 healthy men (20 to 50 yr) undertook consecutive same-day ascents to 25,000 ft (7620 m), following denitrogenation, breathing 100% oxygen. Venous blood was sampled at baseline (T0), after the second ascent (T8), and next morning (T24). Soluble protein markers of brain and lung insult were analyzed by enzyme-linked immunosorbent assay with plasma microparticles quantified using flow cytometry.RESULTS: Levels of monocyte chemoattractant protein-1 and high mobility group box protein 1 were elevated at T8, by 36% and 16%, respectively, before returning to baseline. Levels of soluble receptor for advanced glycation end products fell by 8%, recovering by T24. Brain-derived neurotrophic factor rose by 80% over baseline at T24. Monocyte microparticle levels rose by factors of 3.7 at T8 and 2.7 at T24 due to early and late responses in different subjects. Other biomarkers were unaffected or not detected consistently.DISCUSSION: The elevated biomarkers at T8 suggest a neuroinflammatory response, with later elevation of brain-derived neurotrophic factor at T24 indicating an ongoing neurotrophic response and incomplete recovery. A substantial increase at T8 in the ratio of high mobility group box protein 1 to soluble receptor for advanced glycation end products suggests this axis may mediate the systemic inflammatory response to decompression. The mechanism of neuroinflammation is unclear but elevation of monocyte microparticles and monocyte chemoattractant protein-1 imply a key role for activated monocytes and/or macrophages.Connolly DM, Madden LA, Edwards VC, Lee VM. Brain and lung biomarker responses to hyperoxic hypobaric decompression. Aerosp Med Hum Perform. 2024; 95(9):667-674.

Early Human Pathophysiological Responses to Exertional Hypobaric Decompression Stress.

INTRODUCTION: Consistent blood biomarkers of hypobaric (altitude) decompression stress remain elusive. Recent laboratory investigation of decompression sickness risk at 25,000 ft (7620 m) enabled evaluation of early pathophysiological responses to exertional decompression stress.METHODS: In this study, 15 healthy men, aged 20-50 yr, undertook 2 consecutive (same-day) ascents to 25,000 ft (7620 m) for 60 and 90 min, breathing 100% oxygen, each following 1 h of prior denitrogenation. Venous blood was sampled at baseline (T0), immediately after the second ascent (T8), and next morning (T24). Analyses encompassed whole blood hematology, endothelial microparticles, and soluble markers of cytokine response, endothelial function, inflammation, coagulopathy, oxidative stress, and brain insult, plus cortisol and creatine kinase.RESULTS: Acute hematological effects on neutrophils (mean 72% increase), eosinophils (40% decrease), monocytes (37% increase), and platelets (7% increase) normalized by T24. Consistent elevation (mean five-fold) of the cytokine interleukin-6 (IL-6) at T8 was proinflammatory and associated with venous gas emboli (microbubble) load. Levels of C-reactive protein and complement peptide C5a were persistently elevated at T24, the former by 100% over baseline. Additionally, glial fibrillary acidic protein, a sensitive marker of traumatic brain injury, increased by a mean 10% at T24.CONCLUSIONS: This complex composite environmental stress, comprising the triad of hyperoxia, decompression, and moderate exertion at altitude, provoked pathophysiological changes consistent with an IL-6 cytokine-mediated inflammatory response. Multiple persistent biomarker disturbances at T24 imply incomplete recovery the day after exposure. The elevation of glial fibrillary acidic protein similarly implies incomplete resolution following recent neurological insult.Connolly DM, Madden LA, Edwards VC, D'Oyly TJ, Harridge SDR, Smith TG, Lee VM. Early human pathophysiological responses to exertional hypobaric decompression stress. Aerosp Med Hum Perform. 2023; 94(10):738-749.

Decompression Sickness Risk in Parachutist Dispatchers Exposed Repeatedly to High Altitude.

INTRODUCTION: Occurrences of severe decompression sickness (DCS) in military parachutist dispatchers at 25,000 ft (7620 m) prompted revision of exposure guidelines for high altitude parachuting. This study investigated residual risks to dispatchers and explored the potential for safely conducting repeat exposures in a single duty period.METHODS: In this study, 15 healthy men, ages 20-50 yr, undertook 2 profiles of repeated hypobaric chamber decompression conducting activities representative of dispatcher duties. Phase 1 comprised two ascents to 25,000 ft (7620 m) for 60 and then 90 min. Phase 2 included three ascents first to 25,000 ft for 60 min, followed by two ascents to 22,000 ft (6706 m) for 90 min. Denitrogenation was undertaken at 15,000 ft (4572 m) with successive ascents separated by 1-h air breaks at ground level.RESULTS: At 25,000 ft (7620 m), five cases of limb (knee) pain DCS developed, the earliest at 29 min. Additionally, multiple minor knee "niggles" occurred with activity but disappeared when seated at rest. No DCS and few niggles occurred at 22,000 ft (6706 m). Early, heavy, and sustained bubble loads were common at 25,000 ft, particularly in older subjects, but lighter and later loads followed repeat exposure, especially at 22,000 ft.DISCUSSION: Parachutist dispatchers are at high risk of DCS at 25,000 ft (7620 m) commensurate with their heavy level of exertion. However, the potential exists for repeated safe ascents to 22,000 ft (6706 m), in the same duty period, if turn-around times breathing air at ground level are brief. Older dispatchers (>40 yr) with functional right-to-left (intracardiac or pulmonary) vascular shunts will be at risk of arterialization of microbubbles.Connolly DM, D'Oyly TJ, Harridge SDR, Smith TG, Lee VM. Decompression sickness risk in parachutist dispatchers exposed repeatedly to high altitude. Aerosp Med Hum Perform. 2023; 94(9):666-677.

Hypoxia-Like Events in UK Typhoon Aircraft from 2008 to 2017.

INTRODUCTION: Recent reports of in-flight, hypoxia-like events have prompted concern that aircraft life support systems (LSS) may not always provide effective altitude protection. An analysis was undertaken of hypoxia-like incidents reported in a UK front-line combat aircraft.METHODS: A search of the UK Aviation Safety Information Management System database identified all Typhoon Defense Air Safety Occurrence Reports (DASORs) notifying in-flight symptoms over the decade 20082017. Qualitative analysis focused on the event narrative, altitude profile, timeline, symptom description, sortie characteristics, LSS function, postflight engineering investigation, and training implications. The plausibility and likelihood of hypobaric hypoxia were assessed, and the probable cause of symptoms ascribed.RESULTS: There were 18 DASORs with notified symptoms of suspected in-flight hypoxia, 13 in solo pilots and 5 reports of symptoms affecting 7 of 10 aircrew in 2-seat aircraft. Two cases of probable hypoxia comprised one oxygen bottle failure and one mask-off cabin depressurization. In one report, hypoxia was assessed as plausible but unlikely, following birdstrike with failure of cabin pressurization during climb. Symptoms were explained by hyperventilation in 13 cases (65%) and twice by minor constitutional upset. Suspected hypoxia was managed by immediate selection of emergency oxygen and expedited descent in 10 of 18 occurrences (56%).CONCLUSIONS: Only 2 cases of probable hypoxia have been reported in over 150,000 Typhoon flying hours. The Typhoon LSS has provided effective altitude protection including during cases of cabin depressurization. Symptom occurrences in Typhoon are idiosyncratic and unrelated; hyperventilation probably accounts for two-thirds of reports.Connolly DM, Lee VM, McGown AS, Green NDC. Hypoxia-like events in UK Typhoon aircraft from 2008 to 2017. Aerosp Med Hum Perform. 2021; 92(4):257264.

White Matter Status of Participants in Altitude Chamber Research and Training.

INTRODUCTION: Magnetic resonance imaging (MRI) brain scans of U.S. Air Force (USAF) altitude workers show increased white matter hyperintensities (WMH) that appear related to decompression stress. Relevant exposure thresholds are unknown. This MRI survey compares the white matter status of UK participants (UKP) in altitude chamber research and training with USAF cohorts having background and increased WMH. METHODS: UKP (N = 20) comprised 13 research subjects and 7 military altitude chamber instructors ages 33 to 50 yr (16 men, 4 women), encompassing 1417 decompressions over a 15,000-ft (4572 m) pressure altitude (range 11-189; median 50). High resolution MRI reproduced USAF sequences and data were analyzed at the University of Maryland to validate comparison with age-matched USAF control (DOC; N = 85) and aerospace operational physiologist (PHY; N = 55) cohorts. RESULTS: UKP data are dichotomous: 17 subjects (85%) had normal scans (total 19 WMH) and three outliers had excess (>15) WMH (total of 83 lesions). WMH were not associated with metrics of decompression history (total exposures, rapid decompression, pressure breathing, hypoxia familiarization, decompression sickness, or exposure intensity). Ranked data indicate that UKP have fewer WMH than PHY but not DOC. UKP outliers' excess WMH are attributable to past mild traumatic brain injury. CONCLUSIONS: WMH in UKP are unrelated to subjects' low intensity (brief, infrequent) experience of altitude chamber decompression, encompassing occasional hypobaric hypoxia and mild decompression sickness, even with cumulative experience over many years. Such low intensity hypobaric exposure appears 'subthreshold' for promotion of WMH.Connolly DM, Lee VM, Hodkinson PD. White matter status of participants in altitude chamber research and training. Aerosp Med Hum Perform. 2018; 89(9):777-786.

Odds Ratio Meta-Analysis and Increased Prevalence of White Matter Injury in Healthy Divers.

INTRODUCTION: Increased white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) brain scans of high altitude aircrew and altitude chamber workers indicate that exposure to low ambient pressure (hypobaria) promotes white matter injury. If associated with frequent decompression stress then experienced divers should also exhibit more WMH, yet published case-control studies are inconsistent. This meta-analysis evaluated the prevalence of WMH in healthy divers and controls. METHODS: Eligible studies compared experienced divers (or hyperbaric workers) without neurological decompression illness with nondiving controls, identified from multiple database searches and reference list reviews. Studies were scored for sample size, recruitment bias, control matching, MRI sensitivity, and confounding factors before grading as low, medium, or high quality. Meta-analysis of odds ratios (OR) with 95% confidence intervals (CI) was conducted on all data using a random effects model and repeated after exclusion of low-quality studies. RESULTS: There were 11 eligible studies identified. After data adjustment to exclude diving accidents, these encompassed 410 divers and 339 controls, of which 136 (33%) and 79 (23%), respectively, exhibited WMH (OR 1.925, 95% CI 1.088 to 3.405). Excluding four low-quality studies eliminated meta-analysis heterogeneity, with 98 of 279 divers (35%) and 44 of 232 controls (19%) exhibiting WMH (OR 2.654, 95% CI 1.718 to 4.102). CONCLUSIONS: Results suggest that repeated hyperbaric exposure increases the prevalence of white matter injury in experienced healthy divers without neurological decompression illness. This is consistent with reports of increased WMH in asymptomatic altitude workers and an association with intensity of dysbaric exposure.

Lung volumes, pulmonary ventilation, and hypoxia following rapid decompression to 60,000 ft (18,288 m).

INTRODUCTION: Rapid decompressions (RD) to 60,000 ft (18,288 m) were undertaken by six subjects to provide evidence of satisfactory performance of a contemporary, partial pressure assembly life support system for the purposes of flight clearance. METHODS: A total of 12 3-s RDs were conducted with subjects breathing 56% oxygen (balance nitrogen) at the base (simulated cabin) altitude of 22,500 ft (6858 m), switching to 100% oxygen under 72 mmHg (9.6 kPa) of positive pressure at the final (simulated aircraft) altitude. Respiratory pressures, flows, and gas compositions were monitored continuously throughout. RESULTS: All RDs were completed safely, but one subject experienced significant hypoxia during the minute at final altitude, associated with severe hemoglobin desaturation to a low of 53%. Accurate data on subjects' lung volumes were obtained and individual responses post-RD were reviewed in relation to patterns of pulmonary ventilation. The occurrence of severe hypoxia is explained by hypoventilation in conjunction with unusually large lung volumes (total lung capacity 10.18 L). CONCLUSIONS: Subjects' lung volumes and patterns of pulmonary ventilation are critical, but idiosyncratic, determinants of alveolar oxygenation and severity of hypoxia following RD to 60,000 ft (18,288 m). At such extreme altitudes even vaporization of water condensate in the oxygen mask may compromise oxygen delivery. An altitude ceiling of 60,000 ft (18,288 m) is the likely threshold for reliable protection using partial pressure assemblies and aircrew should be instructed to take two deep 'clearing' breaths immediately following RD at such extreme pressure breathing altitudes.

Decompression sickness risk at 6553 m breathing two gas mixtures.

INTRODUCTION: The risk of severe decompression sickness (DCS) increases rapidly above 6248 m (20,500 ft) and is greater when breathing higher proportions of inert gas. Contemporary aircrew may be exposed to higher cabin altitudes while breathing molecular sieve oxygen concentrator (MSOC) product gas containing variable concentrations of oxygen, nitrogen, and argon. This study assessed the risk of DCS at 6553 m (21,500 ft) breathing two simulated MSOC product gas mixtures. METHODS: In a hypobaric chamber, 10 subjects each undertook 2 4-h exposures at 6553 m breathing either 75% O2:21% N2:4% Ar or 56% 02:42% N2:2% Ar. Subjects undertook regular activities simulating in-flight movements of fast jet aircrew. Venous gas emboli (VGE) "bubble" load was graded every 15 min using 2D and Doppler echocardiography by experienced operators blinded to breathing gas composition. RESULTS: DCS occurred in five exposures (25%), the earliest after less than 90 min at altitude. All were minor, single-site, uncomplicated limb bends that resolved with recompression. VGE occurred in 85% of exposures with some early-onset, heavy loads. Survival (Probit) analysis indicated that breathing 56% oxygen significantly decreased VGE latency relative to breathing 75% oxygen (relative potency 3.05). CONCLUSIONS: From 20 experimental exposures, the risk of DCS at 6553 m is estimated at 5% by 90 min and 20% at 3 h. Exploiting the negative predictive value of VGE latency as a surrogate measure of protection from DCS, at high cabin altitudes better MSOC performance (higher product gas oxygen concentrations) will protect more aircrew for longer.