Susceptibility to high-altitude pulmonary edema is associated with increased pulmonary arterial stiffness during exercise.

High-altitude pulmonary edema (HAPE), a reversible form of capillary leak, is a common consequence of rapid ascension to high altitude and a major cause of death related to high-altitude exposure. Individuals with a prior history of HAPE are more susceptible to future episodes, but the underlying risk factors remain uncertain. Previous studies have shown that HAPE-susceptible subjects have an exaggerated pulmonary vasoreactivity to acute hypoxia, but incomplete data are available regarding their vascular response to exercise. To examine this, seven HAPE-susceptible subjects and nine control subjects (HAPE-resistant) were studied at rest and during incremental exercise at sea level and at 3,810 m altitude. Studies were conducted in both normoxic (inspired Po2 = 148 Torr) and hypoxic (inspired Po2 = 91 Torr) conditions at each location. Here, we report an expanded analysis of previously published data, including a distensible vessel model that showed that HAPE-susceptible subjects had significantly reduced small distal artery distensibility at sea level compared with HAPE-resistant control subjects [0.011 ± 0.001 vs. 0.021 ± 0.002 mmHg-1; P < 0.001). Moreover, HAPE-susceptible subjects demonstrated constant distensibility over all conditions, suggesting that distal arteries are maximally distended at rest. Consistent with having increased distal artery stiffness, HAPE-susceptible subjects had greater increases in pulmonary artery pulse pressure with exercise, which suggests increased proximal artery stiffness. In summary, HAPE-susceptible subjects have exercise-induced increases in proximal artery stiffness and baseline increases in distal artery stiffness, suggesting increased pulsatile load on the right ventricle.NEW & NOTEWORTHY In comparison to subjects who appear resistant to high-altitude pulmonary edema, those previously symptomatic show greater increases in large and small artery stiffness in response to exercise. These differences in arterial stiffness may be a risk factor for the development of high-altitude pulmonary edema or evidence that consequences of high-altitude pulmonary edema are long-lasting after return to sea level.

Repeat exercise normalizes the gas-exchange impairment induced by a previous exercise bout in asthmatic subjects.

Twenty-one subjects with asthma underwent treadmill exercise to exhaustion at a workload that elicited approximately 90% of each subject's maximal O2 uptake (EX1). After EX1, 12 subjects experienced significant exercise-induced bronchospasm [(EIB+), %decrease in forced expiratory volume in 1.0 s = -24.0 +/- 11.5%; pulmonary resistance at rest vs. postexercise = 3.2 +/- 1.5 vs. 8.1 +/- 4.5 cmH2O.l(-1).s(-1)] and nine did not (EIB-). The alveolar-to-arterial Po2 difference (A-aDo2) was widened from rest (9.1 +/- 6.7 Torr) to 23.1 +/- 10.4 and 18.1 +/- 9.1 Torr at 35 min after EX1 in subjects with and without EIB, respectively (P < 0.05). Arterial Po2 (PaO2) was reduced in both groups during recovery (EIB+, -16.0 +/- -13.0 Torr vs. baseline; EIB-, -11.0 +/- 9.4 Torr vs. baseline, P < or = 0.05). Forty minutes after EX1, a second exercise bout was completed at maximal O2 uptake. During the second exercise bout, pulmonary resistance decreased to baseline levels in the EIB+ group and the A-aDo2 and PaO2 returned to match the values seen during EX1 in both groups. Sputum histamine (34.6 +/- 25.9 vs. 61.2 +/- 42.0 ng/ml, pre- vs. postexercise) and urinary 9alpha,11beta-prostaglandin F2 (74.5 +/- 38.6 vs. 164.6 +/- 84.2 ng/mmol creatinine, pre- vs. postexercise) were increased after exercise only in the EIB+ group (P < 0.05), and postexercise sputum histamine was significantly correlated with the exercise PaO2 and A-aDo2 in the EIB+ subjects. Thus exercise causes gas-exchange impairment during the postexercise period in asthmatic subjects independent of decreases in forced expiratory flow rates after the exercise; however, a subsequent exercise bout normalizes this impairment secondary in part to a fast acting, robust exercise-induced bronchodilatory response.

Gas exchange during exercise in habitually active asthmatic subjects.

We determined the relations among gas exchange, breathing mechanics, and airway inflammation during moderate- to maximum-intensity exercise in asthmatic subjects. Twenty-one habitually active (48.2 +/- 7.0 ml.kg(-1).min(-1) maximal O2 uptake) mildly to moderately asthmatic subjects (94 +/- 13% predicted forced expiratory volume in 1.0 s) performed treadmill exercise to exhaustion (11.2 +/- 0.15 min) at approximately 90% of maximal O2 uptake. Arterial O2 saturation decreased to < or =94% during the exercise in 8 of 21 subjects, in large part as a result of a decrease in arterial Po2 (PaO2): from 93.0 +/- 7.7 to 79.7 +/- 4.0 Torr. A widened alveolar-to-arterial Po2 difference and the magnitude of the ventilatory response contributed approximately equally to the decrease in PaO2 during exercise. Airflow limitation and airway inflammation at baseline did not correlate with exercise gas exchange, but an exercise-induced increase in sputum histamine levels correlated with exercise Pa(O2) (negatively) and alveolar-to-arterial Po2 difference (positively). Mean pulmonary resistance was high during exercise (3.4 +/- 1.2 cmH2O.l(-1).s) and did not increase throughout exercise. Expiratory flow limitation occurred in 19 of 21 subjects, averaging 43 +/- 35% of tidal volume near end exercise, and end-expiratory lung volume rose progressively to 0.25 +/- 0.47 liter greater than resting end-expiratory lung volume at exhaustion. These mechanical constraints to ventilation contributed to a heterogeneous and frequently insufficient ventilatory response; arterial Pco2 was 30-47 Torr at end exercise. Thus pulmonary gas exchange is impaired during high-intensity exercise in a significant number of habitually active asthmatic subjects because of high airway resistance and, possibly, a deleterious effect of exercise-induced airway inflammation on gas exchange efficiency.

Role of airway receptors in altitude-induced dyspnea.

PURPOSE: The purpose of this study was to examine the role of airway receptors in respiratory-related sensations after ascent to altitude. METHODS: Ratings of respiratory-related sensations, perceived exertion and acute mountain sickness, heart rate, and peripheral oxygen saturation were recorded at rest and exercise in male and female subjects who had inhaled either aerosolized saline or saline with tetracaine after acute ascent to an altitude of 3500 m and after prolonged acclimatization of 18 d at altitudes between 4000 and 5000 m. RESULTS: Tetracaine had no effect on respiratory-related sensations at altitude either at rest or during exercise, and male and female subjects experienced similar respiratory-related sensations. Sensations of rapid breathing were experienced at rest after acute exposure to 3500 m as compared with sea level, but not after acclimatization to 5000 m. Sensations of rapid breathing, air hunger, and heavy breathing were experienced during exercise after acute and prolonged altitude exposure as compared with sea level, with a sensation of chest tightness experienced at 3500 m and a sensation of gasping experienced at 5000 m. CONCLUSION: These results suggest that airway afferents play no role in the respiratory-related sensations experienced by male and female subjects either during acute ascent to altitude or after prolonged acclimatization at altitude.

Differential effects of airway anesthesia on ozone-induced pulmonary responses in human subjects.

We examined the effect of tetracaine aerosol inhalation, a local anesthetic, on lung volume decrements, rapid shallow breathing, and subjective symptoms of breathing discomfort induced by the acute inhalation of 0.30 ppm ozone for 65 min in 22 ozone-sensitive healthy human subjects. After 50 min of ozone inhalation FEV(1) was reduced 24%, breathing frequency was increased 40%, tidal volume was decreased 31%, and total subjective symptom score was increased (71.2, compared with 3.8 for filtered air exposure). Inhalation of tetracaine aerosol resulted in marked reductions in ozone-induced subjective symptoms of throat tickle and/or irritation (92.1%), cough (78.5%), shortness of breath (72.5%), and pain on deep inspiration (69.4%). In contrast, inhalation of tetracaine aerosol (mass median aerodynamic diameter of 3.52 microm with a geometric standard deviation of 1.92) resulted in only minor and inconsistent rectification of FEV(1) decrements (5.0%) and breathing frequency (-3.8%) that was not significantly different from that produced by saline aerosol alone (FEV(1), 5.1% and breathing frequency, -2.7%). Our data are consistent with afferent endings located within the large conducting airways of the tracheobronchial tree being primarily responsible for ozone-induced subjective symptoms and provides strong evidence that ozone-induced inhibition of maximal inspiratory effort is not dependent on conscious sensations of inspiratory discomfort.

Form and function of fetal and neonatal pulmonary arterial bifurcations.

Bifurcation is a basic form of vascular connection. It is composed of a parent vessel of diameter d(0), and two daughter vessels, d(1) and d(2), where d(0) > d(1) >/= d(2). Optimal values for the bifurcation area ratio, beta = (d(1)(2) + d(2)(2))/d(0)(2), and the junction exponent, x, in d(0)(x) = d(1)(x) + d(2)(x), are postulated to be universal in nature. However, we have hypothesized that the perinatal pulmonary arterial circulation is an exception. Arterial diameters were measured in pulmonary vascular casts of a fetal lamb (140 days gestation/145 days term) and a neonatal lamb (1 day old). The values for beta and x were evaluated in 10,970 fetal and 846 neonatal bifurcations sampled from the proximal and intermediate arterial regions. Mean values and confidence intervals (CI) for the fetus were beta = 0.890 (0.886-0.895 CI) and x = 1.75 (1.74-1.76 CI); and for the newborn were beta = 0.913 (0.90-0.93 CI) and x = 1. 79 (1.75-1.82 CI). These values are significantly different from Murray's law (beta > 1, x = 3) or the West-Brown-Enquist law (beta = 1, x = 2). Therefore, perinatal pulmonary bifurcation design appears to be distinctive and exceptional. The decreasing cross-sectional area with branching leads to the hemodynamic consequence of shear stress amplification. This structural organization may be important for facilitating vascular development at low flow rates; however, it may be the origin of unstable reactivity if elevated blood flow and pressure occurs.

Airway response to concomitant exposure with endotoxin and allergen in atopic asthmatics.

Epidemiological and in vivo studies suggest that inhaled endotoxin may be an important environmental factor associated with the increases in asthma-related morbidity and mortality. Recent studies by our group and others provide a rationale for the hypothesis that airway exposure of atopic asthmatics to both allergen and endotoxin might result in greater inflammatory responses than those observed with either stimulus alone. Moreover, these studies may provide further evidence that concomitant exposure to allergen and endotoxin is an important factor in asthma pathogenesis.

Allergen provocation augments endotoxin-induced nasal inflammation in subjects with atopic asthma.

BACKGROUND: Recent epidemiologic and in vivo studies have suggested that inhaled endotoxin plays an important role in asthma pathogenesis. OBJECTIVE: The present study examines the effect of nasal allergen provocation on subsequent endotoxin challenge in subjects with atopic asthma. METHODS: By using a split-nose randomized crossover design, individual nares of 12 asthmatic subjects underwent challenge and lavage as follows. Immediately after a baseline nasal lavage, one nares received normal saline, and the other received dust mite antigen. Four hours later, both nares were exposed to either saline or endotoxin. Dust mite antigen (Dermatophagoides farinae) and endotoxin (Escherichia coli 026:B6) doses were 100 AU and 1000 ng, respectively. Postchallenge lavages were done at 8 and 24 hours after the initial challenge. The subjects then returned a minimum of 3 weeks later for crossover to the study arm. Nasal lavage fluid was analyzed for total and differential cell counts, IL-8, IL-6, intercellular adhesion molecule 1, GM-CSF, eosinophil cationic protein, myeloperoxidase, and soluble CD14. RESULTS: A significant increase in the total inflammatory cell count was seen at 8 hours for the dust mite/endotoxin exposure compared with the saline/saline and saline/endotoxin exposures. Differential cell counts revealed a similar neutrophilic and eosinophilic inflammation for the dust mite/endotoxin exposure at 8 hours. CONCLUSIONS: These data demonstrate an interaction between allergen and endotoxin exposure in asthmatic subjects, suggesting that a prior allergen challenge significantly augments the endotoxin-induced inflammation. Moreover, these data provide further evidence that concomitant exposure to allergen and endotoxin may be an important factor in asthma pathogenesis.

Multiple organ failure after ingestion of pennyroyal oil from herbal tea in two infants.

BACKGROUND: Hepatic and neurologic injury developed in two infants after ingestion of mint tea. Examination of the mint plants, from which the teas were brewed, indicated that they contained the toxic agent pennyroyal oil. METHODS: Sera from each infant were analyzed for the toxic constituents of pennyroyal oil, including pulegone and its metabolite menthofuran. RESULTS: Fulminant liver failure with cerebral edema and necrosis developed in the first infant, who died. This infant was positive only for menthofuran (10 ng/mL). In the other infant, who was positive for both pulegone (25 ng/mL) and menthofuran (41 ng/mL), hepatic dysfunction and a severe epileptic encephalopathy developed. CONCLUSION: Pennyroyal oil is a highly toxic agent that may cause both hepatic and neurologic injury if ingested. A potential source of pennyroyal oil is certain mint teas mistakenly used as home remedies to treat minor ailments and colic in infants. Physicians should consider pennyroyal oil poisoning as a possible cause of hepatic and neurologic injury in infants, particularly if the infants may have been given home-brewed mint teas.

Pulmonary hemodynamic response to exercise in subjects with prior high-altitude pulmonary edema.

Individuals with a prior history of (susceptible to high altitude pulmonary edema (HAPE-S) have high resting pulmonary arterial pressures, but little data are available on their vascular response to exercise. We studied the pulmonary vascular response to exercise in seven HAPE-S and nine control subjects at sea level and at 3,810 m altitude. At each location, both normoxic (inspired PO2 = 148 Torr) and hypoxic (inspired PO2 = 91 Torr) studies were conducted. Pulmonary hemodynamic measurements included pulmonary arterial and pulmonary arterial occlusion pressures. A multiple regression analysis demonstrated that the pulmonary arterial pressure reactivity to exercise was significantly greater in the HAPE-S group. This reactivity was not influenced by altitude or oxygenation, implying that the response was intrinsic to the pulmonary circulation. Pulmonary arterial occlusion pressure reactivity to exercise was also greater in the HAPE-S group, increasing with altitude but independent of oxygenation. These findings suggest an augmented flow-dependent pulmonary vasoconstriction and/or a reduced vascular cross-sectional area in HAPE-S subjects.

Exercise-induced VA/Q inequality in subjects with prior high-altitude pulmonary edema.

Ventilation-perfusion (VA/Q) mismatch has been shown to increase during exercise, especially in hypoxia. A possible explanation is subclinical interstitial edema due to high pulmonary capillary pressures. We hypothesized that this may be pathogenetically similar to high-altitude pulmonary edema (HAPE) so that HAPE-susceptible people with higher vascular pressures would develop more exercise-induced VA/Q mismatch. To examine this, seven healthy people with a history of HAPE and nine with similar altitude exposure but no HAPE history (control) were studied at rest and during exercise at 35, 65, and 85% of maximum 1) at sea level and then 2) after 2 days at altitude (3,810 m) breathing both normoxic (inspired Po2 = 148 Torr) and hypoxic (inspired Po2 = 91 Torr) gas at both locations. We measured cardiac output and respiratory and inert gas exchange. In both groups, VA/Q mismatch (assessed by log standard deviation of the perfusion distribution) increased with exercise. At sea level, log standard deviation of the perfusion distribution was slightly higher in the HAPE-susceptible group than in the control group during heavy exercise. At altitude, these differences disappeared. Because a history of HAPE was associated with greater exercise-induced VA/Q mismatch and higher pulmonary capillary pressures, our findings are consistent with the hypothesis that exercise-induced mismatch is due to a temporary extravascular fluid accumulation.

The effects of head-down tilt on carotid blood flow and pulmonary gas exchange.

Common carotid artery blood flow (CCF), pulmonary gas exchange and ventilation were measured in six subjects in the supine posture (SUP I), serially during 20 min of head-down tilt at -30 degrees (HDT) and after returning to the supine posture (SUP II). CCF was approximately 6% lower during HDT, with a transient increase during the second minute, and was about 7% higher during SUP II than during SUP I. The transition from SUP I to HDT caused increases in O2 uptake (VO2), CO2 output, respiratory exchange ratio and tidal volume in the first minute. Similar responses were apparent following the HDT to SUP II transition, except for VO2, which changed little. Correction of VO2 for changes in estimated lung O2 stores indicated that about 200 ml of blood were shifted within the circulation by the tilt transitions which provided a ventilatory stimulus. HDT can cause a loss in blood and tissue O2 stores and gain in CO2 stores by shifting blood volume toward and blood flow away from the dependent headward vascular compartment and perhaps by producing ischemia in the elevated lower extremities. Cerebral venous congestion during HDT appears to cause periodic breathing and reduce CCF, the latter being partially offset by reduced flow resistance in the carotid artery.

Sleep apnea and autonomic cerebrovascular dysfunction.

Changes in common carotid blood flow (CCF) and resistance index (RI), calculated from velocity waveforms by a noninvasive pulsed Doppler technique, were measured during apneic episodes and voluntary breath holding in five sleep apnea patients (SA) and during breath holding in five normal subjects (N). During apneic episodes averaging 27 s, CCF was reduced by 9% and RI increased by 4%, both trends being related to apneic duration. Internal carotid artery measurements in one SA indicated more dramatic changes in blood flow and RI than noted in CCF. During breath holding, CCF decreased significantly in SA but not in N, and RI showed a smaller reduction in SA. These changes in CCF and RI during sleep apnea are similar to those noted in anesthetized dogs where vasomotor waves and associated apneas were induced by elevating intracranial pressure. Previously reported recordings of ventilatory and systemic cardiovascular responses in SA are similar to these recordings in dogs, and it is therefore proposed that vasomotor responses to intermittent cerebral ischemia and hypercapnia may be the principle event in SA and periodic breathing only a secondary consequence of the prevailing autonomic dysfunction.

Chronic maternal cigarette smoking and fetal abdominal aortic blood flow in humans.

The abdominal aortic blood flow was measured in 19 fetuses of nonsmoking mothers (NS) and five fetuses of smoking mothers (S) who consumed over 10 cigarettes per day throughout gestation. Serial blood flow measurements beginning in the mid-second trimester to term were made noninvasively with an ultrasonic duplex scanner. Biparietal and transverse abdominal diameters were used to estimate gestational age and fetal weight. Blood velocity spectral waveforms and lumen diameters were used to calculate blood flow (Q, ml/min) and weight normalized blood flow (Q/kg, ml/kg/min). Both Q and Q/kg for the two groups were significantly different by analysis of variance throughout the periods of observation. Third trimester Q and Q/kg (+/- SD) in the S group (738 +/- 20 ml/min and 278 +/- 36 ml/kg/min) were significantly higher (P less than 0.01) than values in the NS group (522 +/- 60 ml/min and 180 +/- 24 ml/kg/min). A redistribution of blood flow to the placenta resulting from an increase in fetal systemic vascular resistance is postulated.

Serial echo-Doppler measurements of human fetal abdominal aortic blood flow.

An echo-Doppler duplex scanner (DS) was used to make serial noninvasive measurements of human fetal abdominal aortic blood flow (Q). In 18 uncomplicated pregnancies (16 weeks to term), Doppler shifted frequency spectral waveforms (delta f), Doppler incident angles (theta), and peak systolic lumen diameters (D) were measured. Using the measured values of delta f and theta, the temporal average blood velocity (V) in the cardiac cycle was calculated from the Doppler equation. Values of Q were calculated using the equation: Q = pi X (D2/2) X V X HR, where HR is the heart rate. Gestational age (GA) and fetal weight (FW) were estimated from biparietal and transverse abdominal diameters. Each fetus was studied three to eight times at 2- to 4-week intervals. Results showed that Q increased nonlinearly with GA. Normalized to estimated FW, values of Q/kg did not vary significantly with estimated GA and gave an overall mean value (+/- standard deviation) during gestation of 184 +/- 35 ml/kg/min.

A comparison of echo-Doppler and electromagnetic renal blood flow measurements.

The linearity and accuracy of noninvasive ultrasonic method of measuring beat-to-beat renal blood flow was evaluated by correlation with standard electromagnetic flowmetry. Using a combined real-time ultrasonic imager and pulsed Doppler velocimeter known as a duplex scanner (DS), lumen diameter (D) and average blood velocity (V) within the imaged renal artery were recorded. Renal blood flow ( QDS ) was calculated offline using a microprocessor from the equation QDS = (pi x D2 x V)/4. This noninvasive method had previously been validated in vitro using a controlled hydraulic system which modeled steady-state flow (QT) where QDS = 0.98 QT + 7.75, SEE = +/- 13.2, r = +0.98, P less than 0.001. In three anesthetized dogs, simultaneous QDS and electromagnetic flow ( QEMF ) measurements (range 44-484 ml x min-1) were made in the proximal left renal artery. Linear regression analysis gave QDS = 0.43 QEMF + 40.5, r = 0.78, SEE = 33.8 ml x min-1, P less than 0.01; QDS = 1.2 QEMF + 2.9, r = 0.86, SEE = 20.8 ml x min-1, P less than 0.01; QDS = 0.86 QEMF + 0.2, r = 0.93, SEE = 53.4 ml x min-1, P less than 0.01. These results suggest that noninvasive QDS measurements of renal blood flow are linear and reasonably accurate compared with invasive QEMF in dogs. The method may have utility in the noninvasive measurement of beat-to-beat blood flow in human renal arteries.

Femoral blood flow in term and premature infants.

A specially designed 20-MHz pulsed Doppler velocity meter was used to quantify noninvasively common femoral artery blood flow and blood flow characteristics in 11 normal term and 12 premature infants. Femoral artery mean velocity (vf), blood flow (Q), weight-normalized blood flow (Q/kg) and pulsatility index (PI) were determined for the two groups. Mean values for Q (+/- SD) in the term and preterm infants were 27.3 +/- 10.3 and 23.4 +/- 14.7 (ml X min-1), respectively (P less than 0.1). Mean Q/kg for the premature infants was significantly higher (22.1 +/- 12.8) than that for the term infants (9.1 +/- 4.2), P less than 0.005. This study demonstrates differences between the pulsatile blood flow and velocity characteristics of the femoral arteries of premature and of full-term infants.

Noninvasive measurement of cardiac output in healthy preterm and term newborn infants.

Although values for cardiac output in the newborn infant have been reported previously, the methods utilized have been invasive. To assess if cardiac output could be determined noninvasively in the neonate, we measured mean ascending aortic blood flow velocity (VAo) in well newborns using a portable 5MHz, range gated, pulsed Doppler velocity meter. Measurements were made from a suprasternal approach in 8 preterm (mean birth weight 1718 gm; mean estimated gestation age 33.3 weeks) and 14 term (mean birthweight 3127 gm; mean EGA 39.8 weeks) healthy infants under one week of age. The internal ascending aortic systolic diameter was determined echographically and aortic cross sectional area was calculated: AAo = pi d2/4. Ascending aortic blood flow (QAo) was then computed as QAo (ml/min) = VAo (cm/sec) X AAo (cm2) X 60 (sec/min). With the exclusion of patent ductus arteriosus (PDA) and detectable intracardiac defects, QAo was taken to equal cardiac output. Flow determinations were normalized to body weight. The 8 preterm infants had a mean cardiac output of 221 +/- 56 (+/- SD) ml/min/kg. The 14 term infants had a similar mean cardiac output of 236 +/- 47 ml/min/kg. The mean cardiac output of all 22 infants was 230 +/- 50. This study establishes normal values for cardiac output determined noninvasively by the Doppler technique, in the first week of life in healthy infants. These values are similar to previously reported systemic blood flows, which were determined by cardiac catheterization and thermodilution methods in healthy newborn infants.

Abnormal cerebrovascular responses to CO2 in sleep apnea patients.

The responses of common carotid blood flow (CCF), pressure (BP), and resistance (R) to variations in respiratory gases were compared during waking periods in 10 sleep apnea patients (SA) and 10 healthy controls (N) of similar age. Respiratory gases were altered by 3-min CO2 rebreathing (RB), 3-min hyperventilation (HV), and 4-min hypoxia (HYP) procedures. CCF was measured continuously by a 5-MHz pulsed Doppler duplex scanner and R was calculated using brachial BP. During RB, which increased end-tidal PCO2 (PACO2) by 15 mm Hg, SA had a lower CCF and greater BP response and therefore a significantly different (positive) change in R compared with N. The ventilatory responses to CO2 were not significantly different. With HV the PACO2 fell by 13 mm Hg in both groups and CCF fell more markedly in SA than N with the same change in BP; therefore, R was increased significantly more in SA. The HYP results did not demonstrate a difference between groups. These results suggest that abnormal cerebrovascular responses to PACO2, initiated either by unusual vasoactive properties of cerebral resistance vessels or peculiar venous outlow patterns, may initiate or potentiate periodic breathing in SA by prolonging lung-to-brain circulation time.