Retrospective Evaluation of Clinical Symptoms Due to Mild Hypobaric Hypoxia Exposure in Microgravity.

INTRODUCTION: A habitat atmosphere of 34% oxygen (O2) and 66% nitrogen (N2) at 8.2 psia (56.5 kPa) is proposed to minimize the risk of decompression sickness during extravehicular activity. The resulting inspired O2 partial pressure (PIo2) of 128 mmHg is similar to that experienced during portions of 41 Space Shuttle missions that used a "staged" denitrogenation (prebreathe) protocol with an atmosphere of 26.5% O2 and 73.5% N2 at 10.2 psia (70.3 kPa). We evaluated symptoms possibly linked to mild hypoxia in astronauts breathing a PIo2 of 127 mmHg. METHODS: Environmental data were used to determine time in the shuttle at 10.2 psia and time at 14.7 psia (101.3 kPa). A total of 14 possible hypoxia symptoms were compared with symptoms collected during normoxic shuttle operations at 14.7 psia using logistic regression. RESULTS: There were 134.1 d (788.8 person days) under the 10.2 psia staged condition with a mean of 3.17 ± 2.2 SD d/mission. There were 258.81 d at 14.7 psia (2192.95 person days). An average of 4.31 potentially hypoxia-related symptoms per mission day was documented under the staged condition compared with 4.08 per mission day during the normoxic condition. Logistic regression showed no symptoms were significantly associated with just the 10.2 psia condition. DISCUSSION: Chronic exposure to a PIo2 of 127 mmHg is well-tolerated by healthy humans on Earth. A similar short-duration exposure on the shuttle resulted in no increased reporting of possible hypoxia-related symptoms. However, chronic mild hypoxia interactions with physiological changes due to microgravity adaptations remain unclear.Wessel JH III, Schaefer CM, Thompson MS, Norcross JR, Bekdash OS. Retrospective evaluation of clinical symptoms due to mild hypobaric hypoxia exposure in microgravity. Aerosp Med Hum Perform. 2018; 89(9):792-797.

Venous Gas Emboli and Ambulation at 4.3 psia.

INTRODUCTION: Ambulation during extravehicular activity on Mars may increase the risk of decompression sickness through enhanced bubble formation in the lower body. HYPOTHESES: walking effort (ambulation) before an exercise-enhanced denitrogenation (prebreathe) protocol at 14.7 psia does not increase the incidence of venous gas emboli (VGE) at 4.3 psia, but does increase incidence if performed after tissues become supersaturated with nitrogen at 4.3 psia. METHODS: VGE results from 45 control subjects who performed exercise prebreathe without ambulation before or during a 4-h exposure to 4.3 psia were compared to 21 subjects who performed the same prebreathe but ambulated before and during the hypobaric exposure (Group I) and to 41 subjects who only ambulated before the hypobaric exposure (Group II). Monitoring for VGE in the pulmonary artery was for 4 min at about 12-min intervals using precordial Doppler ultrasound (2.5 mHz). Detected VGE were assigned a categorical grade from I to IV. The detection of Grade III or IV was classified as "high VGE grade." RESULTS: The incidence of high VGE grade for Group I (57%) was greater than the control (17%) and Group II (15%). The incidence of pain-only decompression sickness was greater for Group I (20%) than the control (0%) and Group II (5%). CONCLUSIONS: High-grade VGE are increased by mild ambulation conducted under a supersaturated state (Group I vs. II); however, no increase was observed with mild ambulation during the saturated state alone (control vs. Group II).Conkin J, Pollock NW, Natoli MJ, Martina SD, Wessell JH III, Gernhardt ML. Venous gas emboli and ambulation at 4.3 psia. Aerosp Med Hum Perform. 2017; 88(4):370-376.

Hemoglobin Oxygen Saturation with Mild Hypoxia and Microgravity.

INTRODUCTION: Microgravity (µG) exposure and even early recovery from µG in combination with mild hypoxia may increase the alveolar-arterial oxygen (O2) partial pressure gradient. METHODS: Four male astronauts on STS-69 (1995) and four on STS-72 (1996) were exposed on Earth to an acute sequential hypoxic challenge by breathing for 4 min 18.0%, 14.9%, 13.5%, 12.9%, and 12.2% oxygen-balance nitrogen. The 18.0% O2 mixture at sea level resulted in an inspired O2 partial pressure (PIo2) of 127 mmHg. The equivalent PIO2 was also achieved by breathing 26.5% O2 at 527 mmHg that occurred for several days in µG on the Space Shuttle. A Novametrix CO2SMO Model 7100 recorded hemoglobin (Hb) oxygen saturation through finger pulse oximetry (Spo2, %). There were 12 in-flight measurements collected. Measurements were also taken the day of (R+0) and 2 d after (R+2) return to Earth. Linear mixed effects models assessed changes in Spo2 during and after exposure to µG. RESULTS: Astronaut Spo2 levels at baseline, R+0, and R+2 were not significantly different from in flight, about 97% given a PIo2 of 127 mmHg. There was also no difference in astronaut Spo2 levels between baseline and R+0 or R+2 over the hypoxic challenge. CONCLUSIONS: The multitude of physiological changes associated with µG and during recovery from µG did not affect astronaut Spo2 under hypoxic challenge.Conkin J, Wessel JH III, Norcross JR, Bekdash OS, Abercromby AFJ, Koslovsky MD, Gernhardt ML. Hemoglobin oxygen saturation with mild hypoxia and microgravity. Aerosp Med Hum Perform. 2017; 88(6):527-534.

Hypobaric Decompression Sickness Treatment Model.

INTRODUCTION: The Hypobaric Decompression Sickness (DCS) Treatment Model links a decrease in computed bubble volume from increased pressure (ΔP), increased oxygen (O2) partial pressure, and passage of time during treatment to the probability of symptom resolution [P(SR)]. The decrease in offending volume is realized in two stages: 1) during compression via Boyles law; and 2) during subsequent dissolution of the gas phase via the oxygen window. METHODS: We established an empirical model for the P(SR) while accounting for multiple symptoms within subjects. The data consisted of 154 cases of hypobaric DCS symptoms with ancillary information from tests on 56 men and 18 women. RESULTS: Our best estimated model is P(SR)=1/(1+exp(-(ln(ΔP)-1.510+0.795×AMB-0.00308×Ts)/0.478)), where ΔP is pressure difference (psid); AMB=1 if ambulation took place during part of the altitude exposure, otherwise AMB=0; and Ts is the elapsed time in minutes from the start of altitude exposure to recognition of a DCS symptom. DISCUSSION: Values of ΔP as inputs to the model would be calculated from the Tissue Bubble Dynamics Model based on the effective treatment pressure: ΔP=P2-P1|=P1×V1/V2-P1, where V1 is the computed volume of a bubble at low pressure P1 and V2 is computed volume after a change to a higher pressure P2. If 100% ground-level oxygen was breathed in place of air, then V2 continues to decrease through time at P2 at a faster rate.

Critique of the equivalent air altitude model.

The adverse effects of hypoxic hypoxia include acute mountain sickness (AMS), high altitude pulmonary edema, and high altitude cerebral edema. It has long been assumed that those manifestations are directly related to reduction in the inspired partial pressure of oxygen (P(I)O2). This assumption underlies the equivalent air altitude (EAA) model, which holds that combinations of barometric pressure (P(B)) and inspired fraction of O2 (F(I)O2) that produce the same P(I)O2 will result in identical physiological responses. However, a growing body of evidence seems to indicate that different combinations of P(B) and P(I)O2 may produce different responses to the same P(I)O2. To investigate this question with respect to AMS, we conducted a search of the literature using the terms hypobaric hypoxia, normobaric hypoxia, and hypobaric normoxia. The results suggest that the EAA model provides only an approximate description of isohypoxia, and that P(B) has an independent effect on hypoxia and AMS. A historical report from 1956 and 15 reports from 1983 to 2005 compare the same hypoxic P(I)O2 at different P(B) with respect to the development of hypoxia and AMS. These data provide evidence for an independent effect of P(B) on hypoxia and AMS, and thereby invalidate EAA as an ideal model of isohypoxia. Refinement of the EAA model is needed, in particular for applications to high altitude where supplemental O2 is inadequate to prevent hypoxic hypoxia. Adjustment through probabilistic statistical modeling to match the current limited experimental observations is one approach to a better isohypoxic model.

Diurnal rhythms of tryptophan hydroxylase 1 and 2 mRNA expression in the rat retina.

Tryptophan hydroxylase is the first of four enzymes in the melatonin biosynthetic pathway. Recent studies have shown that there are two genes, Tph1 and Tph2, that encode tryptophan hydroxylase in mammals. In this study, we investigated which of the two genes is expressed in the rat retina. To that end, we measured Tph1 (classical Tph) and Tph2 mRNA levels using real-time quantitative RT-PCR in the retina. Our data demonstrate that Tph1 mRNA is the prevalent form expressed in the retina; Tph2 mRNA is also present but the level is very low. We also measured Tph1 expression levels in the outer nuclear layer, inner nuclear layer, and ganglion cell layer by combining laser capture microdissection and real-time RT-PCR. Tph1 mRNA is more abundant in the photoreceptors of the outer nuclear layer than in the inner nuclear layer or ganglion cell layer. Tph1 and Tph2 transcripts showed robust diurnal rhythms of abundance, with highest levels at night. Our results support the hypothesis that Tph1 is involved in melatonin synthesis in retinal photoreceptor cells.

Localization of Aa-nat mRNA in the rat retina by fluorescence in situ hybridization and laser capture microdissection.

Arylalkylamine N-acetyltransferase (AA-NAT) is the key regulatory enzyme in the melatonin biosynthetic pathway. Previous investigations have reported that Aa-nat mRNA in rat is only detected in a sub-population of photoreceptor cells that resemble cones in shape and size. In the present study, we investigated Aa-nat expression in the rat retina by using in situ hybridization and laser capture microdissection combined with the reverse transcription/polymerase chain reaction technique. Our results demonstrate that, contrary to previous reports, Aa-nat transcripts are present not only in the photoreceptor cells, but also in the inner nuclear layer and in the ganglion cell layer. However, the rhythmic expression of Aa-nat mRNA was observed only in photoreceptor cells.

Dual regulation of cryptochrome 1 mRNA expression in chicken retina by light and circadian oscillators.

The localization and regulation of chicken cryptochrome 1 (cCry1) mRNA expression in retina was investigated by laser capture microdissection and quantitative real-time RT-PCR. Laser capture microdissection (LCM) of retinal cell layers showed the highest level of cCry1 expression in the ganglion cell and photoreceptor layers. In both layers, expression was high during the daytime and low at night in subjects exposed to a 12:12 h light:dark cycle. Robust circadian oscillations of cCry1 mRNA levels were observed in constant (24 h day) light, but not in constant darkness, with the highest expression during daytime at zeitgeber time (ZT) 8. Unlike cCry1, circadian rhythms of the melatonin-synthesizing enzyme, arylalkylamine N-acetyltransferase, persisted in constant darkness, suggesting that rhythmic cCry1 expression is not essential for circadian clock function or output. On the second day of constant darkness, when cCry1 expression is arrhythmic, light exposure for 2 h significantly increased retinal cCry1 mRNA levels at ZT 4 and 8, times that cCry1 expression is induced in LD and LL. Similar light exposure ending at ZT 20 had no significant effect. Thus, expression of cCry1 mRNA is regulated dually by light and circadian clocks.