Patent foramen ovale: a review of associated conditions and the impact of physiological size.

Patent foramen ovale (PFO) is implicated in platypnea-orthodeoxia, stroke and decompression sickness (DCS) in divers and astronauts. However, PFO size in relation to clinical illness is largely unknown since few studies evaluate PFO, either functionally or anatomically. The autopsy incidence of PFO is approximately 27% and 6% for a large defect (0.6 cm to 1.0 cm). A PFO is often associated with atrial septal aneurysm and Chiari network, although these anatomic variations are uncommon. Methodologies for diagnosis and anatomic and functional sizing of a PFO include transthoracic echocardiography (TTE), transesophageal echocardiography (TEE) and transcranial Doppler (TCD), with saline contrast. Saline injection via the right femoral vein appears to have a higher diagnostic yield for PFO than via the right antecubital vein. Saline contrast with TTE using native tissue harmonics or transmitral pulsed wave Doppler have quantitated PFO functional size, while TEE is presently the reference standard. The platypnea-orthodeoxia syndrome is associated with a large resting PFO shunt. Transthoracic echocardiography, TEE and TCD have been used in an attempt to quantitate PFO in patients with cryptogenic stroke. The larger PFOs (approximately > or =4 mm size) or those with significant resting shunts appear to be clinically significant. Approximately two-thirds of divers with unexplained DCS have a PFO that may be responsible and may be related to PFO size. Limited data are available on the incidence of PFO in high altitude aviators with DCS, but there appears to be a relationship. A large decompression stress is associated with extra vehicular activity (EVA) from spacecraft. After four cases of serious DCS in EVA simulations, a resting PFO was detected by contrast TTE in three cases. Patent foramen ovales vary in both anatomical and functional size, and the clinical impact of a particular PFO in various situations (platypnea-orthodeoxia, thromboembolism, DCS in underwater divers, DCS in high-altitude aviators and astronauts) may be different.

Immersed false vertical room. A new motion sickness model.

We evaluated a new model of motion sickness--an enclosure decorated with visual cues to upright which was immersed either inverted or "front"-wall down, in Johnson Space Center's Weightless Environment Training Facility (WETF) pool. This "WETF False Vertical Room" (WFVR) was tested with 19 male and 3 female SCUBA diver subjects, aged 23 to 57, who alternately set clocks mounted near the room's 8 corners and made exaggerated pitch head movements. We found that (1) the WFVR test runs produced motion sickness symptoms in 56% and 36% of subjects in the room-inverted and room-front-down positions, respectively. (2) Pitch head movements were the most provocative acts, followed closely by setting the clocks--particularly when a clock face filled the visual field. (3) When measured with a self-ranking questionnaire, terrestrial motion sickness susceptibility correlated strongly (P < 0.005) with WFVR sickness susceptibility. (4) Standing instability, measured with a modified Fregly-Graybiel floor battery, also correlated strongly (P < 0.005) with WFVR sickness susceptibility. This result may reflect a relationship between visual dominance and WFVR sickness. (5) A control study demonstrated that the inverted and front-down positions produced WFVR sickness, but the upright position did not, and that adaptation may have occurred in some subjects with repeated exposure. The WFVR could become a useful terrestrial model of space motion sickness (SMS) because it duplicates the nature of the gravity-dependent sensory conflicts created by microgravity (visual and otolith inputs conflict while somatosensory gravity cues are minimized), and it also duplicates the nature of the provocative stimulus (sensory environment "rule change" versus application of motion to passive subject) more closely than any other proposed terrestrial SMS model. Also, unlike any other proposed terrestrial SMS model, the WFVR incorporates whole-body movement in all three spatial dimensions. However, the WFVR's sensory environment differs from that created by spaceflight in several respects, including the presence of frictional drag on limb movement, magnification at the face-mask-water interface, greater otolith conflict, exhaled bubbles, and the presence of some gravity-dependent somatosensory inputs.

Inverted immersion as a novel gravitoinertial environment.

BACKGROUND: Inverted immersion (II) offers a unique opportunity to swing the orientation of the gravity vector 180 degrees from its usual configuration with vestibular end organs. During II, extrathoracic fluid dynamics are identical to those of upright immersion (UI). II exposes individuals to a novel gravitoinertial environment and, therefore, should produce motion sickness (MS). HYPOTHESIS: II is more provocative of signs and symptoms of MS than UI. METHODS: Nine subjects were exposed once to II and UI. Conventional SCUBA gear was worn. In II, the subject wore a wetsuit which provided 5-7 kg force of positive buoyancy and, with no weight belt, caused him to float while inverted against the underside of a platform. An experiment with UI was identical except that a weight belt was worn which provided 5-7 kg force of negative buoyancy, and the subject stood upright against the bottom of the pool. The experiment was terminated after 3 hours or "upon the onset of the first, clear, persistent feeling of nausea", whichever came first. Throughout the experiment the subject rotated through a series of tasks: assembly of a pipe puzzle, performance of a series of head movements, and ambulation. Immediately post-dive, postural stability was assessed with tandem standing with and without eyes closed and with and without the neck extended 45 degrees. A questionnaire regarding susceptibility to motion sickness was completed pre-dive. RESULTS: No subject terminated the test because of MS during UI; seven subjects terminated the test during II (p < 0.025, McNemar's test). Posture was less stable after II than after UI (p < 0.05, sign test). MS questionnaire results did not predict susceptibility to II. CONCLUSION: II is provocative of MS and postural instability.

Patent foramen ovale and hypobaric decompression.

Gas microbubbles were detected in the left ventricle of a supine subject being screened for an atrial septal defect as a participant of a hypobaric decompression study. This determination was made using the saline echocontrast procedure. We found provocation by a Valsalva maneuver not to be necessary in this individual for right-to-left passage of contrast microbubbles into the left heart and middle cerebral artery. When this same individual underwent hypobaric decompression to a simulated altitude of 21,000 ft, numerous gas microbubbles were detected in the right heart, but no gas bubbles were detected in either the left ventricular outflow tract or in the middle cerebral artery. This observation appears to be a novel finding, not previously reported.

Physiologically and subjectively acceptable breathing resistance in divers' breathing gear.

To determine acceptable levels of breathing resistance in divers' gear, 6 subjects were exposed to varying levels of breathing resistance under demanding and realistic conditions. The immersed air-breathing subjects exercised in the prone position at 60% of their maximum oxygen uptake for 25 min in a hyperbaric chamber at 1.45 and 6.8 atm abs (145 and 690 kPa, 4.5 and 57 msw, 15 and 190 fsw). The breathing resistance ranged from minimal to 8-12 cmH2O (0.8-1.2 kPa).liter-1.s at flow rates of 2-3 liter/s. The higher resistance levels interfered with the respiration in terms of end-tidal PCO2 and dyspnea scores. There were considerable individual differences, and changes in one parameter were typically not paralleled by changes in the other. None of maximal voluntary ventilation, forced expiratory volume, expiratory reserve volume, vital capacities, or oxygen uptake was influenced by resistance. We set the maximum allowable end-tidal PCO2 at 60 mmHg and maximum dyspnea score at 1.0 on a scale from 0 (none) to 3 (severe). Based on these criteria we concluded that the external work of breathing should not exceed 1.5-2.0 J/liter in the ventilation range 30 to 75 liter/min BTPS.

Susceptibility of divers in open water to motion sickness.

Several aspects of the environment of divers should increase their susceptibility to motion sickness: a) sensory conflicts, b) body fluid redistribution, and c) nitrogen narcosis. We tested motion sickness susceptibility by placing subjects on a rotating platform and having them perform stylized heat movements that produced cross-coupled angular accelerations in vestibular end organs until nausea developed. This test was performed once each day on 9 consecutive days while subjects were immersed at the end of 3-4 h of diving. The test was also carried out while subjects were nonimmersed with no preceding diving on the day immediately before and after this 9-day period. Compared with nonimmersed conditions, significantly fewer head movements were required to elicit nausea while immersed (P less than 0.01). We conclude that individuals are more susceptible to motion sickness while immersed in open water than while on dry land.

Treatment of motion sickness in parabolic flight with buccal scopolamine.

Treatment of acute motion sickness induced by parabolic flight with a preparation of scopolamine placed in the buccal pouch was investigated. Twenty-one subjects flew aboard a KC-135 aircraft operated by the National Aeronautics and Space Administration (NASA) which performed parabolic maneuvers resulting in periods of 0-g, 1-g, and 1.8-g. Each subject flew once with a tablet containing scopolamine and once with a placebo in a random order, crossover design. Signs and symptoms of motion sickness were systematically recorded during each parabola by an investigator who was blind to the content of the tablet. Compared with flights using placebo, flights with buccal scopolamine resulted in significantly lower scores for nausea (31%-35% reduction) and vomiting (50% reduction in number of parabolas with vomiting). Side effects of the drug during flight were negligible. We conclude that buccal scopolamine is more effective than a placebo in treating ongoing motion sickness.

O2 pressures between 0.12 and 2.5 atm abs, circulatory function, and N2 elimination.

To study the effects of inhaled oxygen pressures on N2 elimination, 72, 2-h washouts were performed in 6 subjects at oxygen pressures of 0.12, 0.2, 1.0, 2.0, and 2.5 atm abs using a closed circuit system that supplied an O2-argon mixture and collected the N2 off-gassed. Hypoxia induced a significant (9.4%, P less than 0.05) increase in nitrogen eliminated as compared to normoxia. Pure oxygen breathing induced a small, insignificant (3.5%) decrease in nitrogen yields, but further increases in oxygen pressure induced significant decreases in nitrogen yields (-8.9% and -16.9% for 2.0 and 2.5 atm abs, respectively). Heart rate, cardiac output, skin perfusion and leg blood flow decreased, whereas mean arterial pressure increased with increasing oxygen pressure. We conclude, therefore, that perfusion-dependent N2 elimination decreases secondary to vasoconstriction induced by increasing oxygen pressures. Changes in inhaled oxygen pressures during different phases of compression-decompression may induce alterations in the rate of inert gas uptake and elimination. Although not currently quantifiable, such alterations would imply added uncertainties in the computation of decompression schedules. Oxygen breathing during decompression should be performed at the lowest possible ambient pressure compatible with freedom from pathogenic bubble formation.

CO2 retention with minimal symptoms but severe dysfunction during wet simulated dives to 6.8 atm abs.

During wet dives in a hyperbaric chamber to 6.8 atm abs (690 kPa), air breathing subjects were experimentally exposed to external breathing resistance. Two of them were, unbeknownst to themselves, severely incapacitated. In the first incident the subject had been exercising for 25 min (end-tidal PCO2 60-65 mmHg, 7.3-8.0 kPa) when the breathing resistance was rapidly increased from low to very high (requiring pressure swings of 80 cmH2O, 8 kPa, peak to peak). He functioned normally (end-tidal PCO2 72 mmHg, 9.6 kPa) for about 100 s but 20 s later he was confused and irrational. After being extracted from the water (end-tidal PCO2 above 90 mmHg, 12 kPa), he lost consciousness for about 60 s. In the second incident the subject was exercising and breathing against a high resistance (pressure swings of 50-55 cmH2O, 5.0-5.6 kPa). His end-tidal PCO2 was high (65-68 mmHg, 8.7-9.3 kPa) throughout the exercise period, and after 24 min he reported mild dyspnea. A few seconds later he became confused. In other experiments both subjects voluntarily terminated experiments when the breathing resistance became overwhelming. These 2 subjects generally had high end-tidal PCO2 levels, but 1 other subject with end-tidal PCO2 levels in the same range never experienced any problems. These incidents indicate that severe hypercapnia does not necessarily correlate with dyspnea and that severe disturbances in mental function due to hypercapnia can develop suddenly when high breathing resistance is encountered in diving.

Indomethacin does not diminish the pulmonary vascular response of the fetus to increased oxygen tension.

This study was performed to determine whether prostaglandins play a role in the increase in pulmonary blood flow in the fetal lamb caused by an increase in oxygen tension similar to that occurring at birth. To increase fetal oxygen tension without ventilating the lungs, nine pregnant ewes with chronically instrumented fetuses were exposed to 100% oxygen at 3 atmospheres absolute pressure for 20 min in a hyperbaric chamber. This exposure increased pulmonary arterial oxygen tension in the nine fetuses from 20 +/- 1 to 54 +/- 9 torr. It increased pulmonary blood flow from fetal to newborn values, 31 +/- 3 to 295 +/- 20 ml/kg/min. It did not change pulmonary arterial pressure, 52 +/- 2 torr during normoxia and 50 +/- 2 torr during hyperoxia. Treating five of these fetuses with 3.2 +/- 0.4 mg/kg of indomethacin during hyperbaric oxygenation did not alter these effects (PO2 = 51 +/- 8 torr, pulmonary blood flow = 283 +/- 13 ml/kg/min, and pulmonary arterial pressure = 48 +/- 2 torr). We conclude that the increase in pulmonary blood flow caused by an increase in oxygen tension in the fetus is not maintained by prostaglandins.

Can eucapnic hyperventilation prolong a subsequent breath-hold?

Previous studies have shown that, upon breaking a maximal breath-hold (BH), reinhalation of the expired gas allows an additional period of breath-holding. This indicates that mere ventilatory movements can diminish the urge to breathe. We sought to determine if vigorous ventilations, performed immediately prior to a maximal BH and in such a way that CO2 stores are not changed, can prolong a subsequent BH. Maximal BHs were accomplished with and without a preceding period of hyperventilation. The gas breathed during hyperventilation was air with 4.37% CO2, or oxygen containing either 0.04% CO2 (hypocapnic hyperventilation) or 4.37% CO2 (eucapnic hyperventilation). During hyperventilation, expired minute volume and frequency were clamped at 60 L/min and 30 breaths/min, respectively. End-tidal and transcutaneous CO2 tensions were monitored. Eucapnic hyperventilation did not prolong maximal BHs. Therefore, the ventilatory movements of hyperventilation do not appear to affect the duration of a subsequent maximal BH if these movements are not accompanied by changes in CO2 stores.

A comparison of respiratory function in divers breathing with a mouthpiece or a full face mask.

A comparison was made of respiratory function in submersed divers breathing with either a mouthpiece or a full face mask while exposed to varying depths (15 and 190 fsw), exercise loads (0-175 W), and static lung loads (0 and -20 cmH2O). The two types of breathing equipment were designed to be identical in terms of functional dead space volume and resistance to gas flow. When compared with data from experiments utilizing a full face mask, use of a mouthpiece caused a modest fall in expired minute volume at both depths. The majority of this decline may have been the consequence of a decrease in dead space ventilation brought about by the elimination of simultaneous nose breathing and mouth breathing. Alveolar ventilation and PETCO2 were not significantly influenced by the use of a mouthpiece, regardless of depth, workload, or static lung load. With both types of breathing gear episodes of dyspnea were infrequent during experiments with a static lung load of 0 cmH2O. Therefore, if a neutral static lung load is maintained, the type of breathing gear used does not seem to be of consequence as far as dyspnea is concerned.

Respiratory function in the upright, working diver at 6.8 ATA (190 fsw).

The influence of static lung loading on a number of respiratory parameters was investigated in subjects performing graded leg exercise in an upright posture while submerged and breathing air at ambient pressures up to 6.76 ATA. In comparison with a previous investigation of the prone posture, a lesser tendency to dyspnea was observed. Neutral and moderately positive static lung loads were associated with less dyspnea than were negative loads. Several indices of respiratory function remained relatively normal during exercise and exposure to varying static lung loads. However, there was a tendency for hypoventilation and CO2 accumulation during heavy exercise at 190 fsw; this was not strictly correlated with dyspnea or static lung load. We conclude that, if a full face mask is used, breathing gear for divers should provide a static lung load of approximately 0 to +10 cmH2O regardless of the diver's orientation in the water. When possible, divers should assume an upright posture while engaged in strenuous work.

Adaptations of alpha2- and beta-cells of rat and mouse pancreatic islets to starvation, to refeeding after starvation, and to obesity.

The effects of starvation and refeeding and of obesity on pancreatic alpha2- and beta-cell responses to glucose or tolbutamide were studied with the isolated rat or mouse pancreas perfused with an amino acid mixture in the presence and absence of glucose. It was observed that the physiological adaptation to a regimen of fasting and realimentation and to obesity differed greatly in the two types of endocrine cells. Whereas beta-cells of rats showed a dramatic reduction of glucose- and tolbutamide-stimulated insulin release during starvation that was reversed by refeeding, alpha2-cells preserved their response to stimulators and inhibitors during this experimental manipulation. Amino acid stimulation of glucagon release occurred equally well with the pancreas from fed and starved rats and was suppressed efficiently by glucose and tolbutamide in both nutritional states. Surprisingly, the rate of onset of glucose suppression of alpha2-cells was significantly higher in the fasted than in the fed state. This glucose hypersensitivity was apparent 2 d after after food deprivation and had disappeared again on the 2nd d of refeeding. In the pancreas from animals starved for 3 d, glucose and tolbutamide suppression of alpha2-cells took place in the absence of demonstrable changes of insulin release. In the isolated perfused pancreas taken from the hyperphagic obese hyperglycemic mouse (C57 Black/6J; ob/ob), the observed rate of insulin secretion as a result of a combined stimulus of amino acids and glucose and of glucagon release stimulated by amino acids was about four times higher than achieved by the pancreas of lean controls. However, glucose was unable to suppress the alpha2-cells in the pancreas of obese animals, in spite of the hypersection of the beta-cells, again in contrast to the alpha2-cells of controls that were readily inhibited by glucose. These data imply that the acute suppression of alpha2-cells by glucose is largely independent of a concomitant surge of extracellular insulin levels and that the adaptation of the islet organ to starvation leads to decreased glucose sensitivity of beta-cells, which contrasts with an improved glucose responsiveness of alpha2-cells. However, hyperphagia, which is assumed to be the primary abnormality in the ob/ob mouse, leads to overproduction of insulin and glucagon by the pancreas while greatly reducing the alpha2-cell sensitivity to glucose. An attempt is made to incorporate these data on starvation, refeeding, and obesity, as well as previous results with experimental diabetes, in a comprehensive picture describing a regulative principle underlying the glucose responsivness of alpha2-cells.

Comparison of alpha- and beta-cell secretory responses in islets isolated with collagenase and in the isolated perfused pancreas of rats.

The inhibitory actions of somatostatin (100 ng./ml.) on insulin release, stimulated by high glucose (20 mM), and on glucagon release, stimulated by arginine (15 mM), were studied with two in vitro systems: the isolated perifused rat islets prepared by the collagenase procedure and the isolated perfused rat pancreas. Suppression of arginine-induced glucagon release by glucose (20 mM) and glyceraldehyde (5 mM) was also assessed in both systems. With the perfused pancreas, somatostatin caused 32 per cent inhibition of glucose-mediated insulin release and inhibited arginine-induced glucagon release by 72 per cent. In the same system, glucose and glyceraldehyde were similarly potent inhibitors of arginine-induced glucagon secretion. In contrast to the isolated perfused pancreas, there was no significant somatostation suppression of glucose-induced insulin release or arginine-induced glucagon release whether the inhibitor was present prior to or was added during stimulation by glucose or arginine. Furthermore, glucose was only minimally active and glyceraldehyde ineffective in inhibiting glucagon secretion due to arginine in the perifusion system. The most plausible explanation for the difference in the endocrine response of islet cells in the two types of widely used in vitro systems is that the alpha and beta cells have lost inhibitory receptors in the plasma membrane as a result of the collagenase isolation technic.