Revised one-step method for determination of cardiac output.

Cardiac output (Q) is a determinant of blood pressure and O(2) delivery and is critical in the maintenance of homeostasis, particularly during environmental stress and exercise. Cardiac output can be determined invasively in patients; however, indirect methods are required for other situations. Soluble gas techniques are widely used to determine (Q). Historically, measurements during a breathhold, prolonged expiration and rebreathing to CO(2) equilibrium have been used; however, with limitations, especially during stress. Farhi and co-workers developed a single-step CO(2) rebreathing method, which was subsequently revised by his group, and has been shown to be reliable and compared closely to direct, invasive measures. V(CO2), P(ACO2), and P(VCO2) are determined during a 12-25s rebreathing, using the appropriate tidal volume, and (Q) is calculated. This method can provide accurate data in laboratory and field experiments during exercise, increased or decreased gravity, water immersion, lower body pressure, head-down tilt, altered ambient pressure or changes in inspired gas composition.

Cardiac output: a view from Buffalo.

Cardiac output (Q) is a primary determinant of blood pressure and O2 delivery and is critical in the maintenance of homeostasis, particularly during environmental stress. Cardiac output can be determined invasively in patients; however, indirect methods are required for other situations. Soluble gas techniques are widely used to determine Q. Historically, measurements during a breathhold, prolonged expiration and rebreathing to CO2 equilibrium have been used; however, with limitations, especially during stress. Farhi and co-workers developed a single-step CO2 rebreathing method, which was subsequently revised by his group, and has been shown to be valid (compared to direct measures) and reliable. Carbon dioxide output (VCO2), partial pressure of arterial CO2 (PaCO2), and partial pressure of mixed venous CO2 (Pv(CO2)) are determined during 12-25 s of rebreathing, using the appropriate tidal volume, and Q is calculated. This method has the utility to provide accurate data in laboratory and field experiments during exercise, increased and micro-gravity, water immersion, lower body pressure, head-down tilt, and changes in gas composition and pressure. Utilizing the Buffalo CO2 rebreathing method it has been shown that the Q can adjust to a wide range of changes in environments maintaining blood pressure and O2 delivery at rest and during exercise.

Cardiovascular response to submaximal exercise in sustained microgravity.

Cardiac output (Q), heart rate (HR), blood pressure, and oxygen consumption (VO2) were measured repeatedly both at rest and at two levels of exercise in six subjects during microgravity exposure. Exercise was at 30 and 60% of the workload producing the individual's maximal VO2 in 1 G. Three of the subjects were on a 9-day flight, Spacelab Life Sciences-1, and three were on a 15-day flight, Spacelab Life Sciences-2. We found no temporal differences during the flights. Thus we have combined all microgravity measurements to compare in-flight values with erect or supine control values. At rest, Q in flight was 126% of Q erect (P < 0.01) but was not different from Q supine, and HR in flight was 81% of HR erect (P < 0.01) and 91% of HR supine (P < 0.05). Thus resting stroke volume (SV) in flight was 155% of SV erect (P < 0.01) and 109% SV supine (P < 0.05). Resting mean arterial blood pressure and diastolic pressure were lower in flight than erect (P < 0.05). Exercise values were considered as functions of VO2. The increase in Q with VO2 in flight was less than that at 1 G (slope 3.5 vs. 6.1 x min-1.l-1.min-1). SV in flight fell with increasing VO2, whereas SV erect rose and SV supine remained constant. The blood pressure response to exercise was not different in flight from erect or supine. We conclude that true microgravity causes a cardiovascular response different from that seen during any of its putative simulations.

Cardiorespiratory response to lower body negative pressure.

The cardiovascular effects of supine lower body negative pressure (LBNP, 0 mm Hg, -8 mm Hg, -15 mm Hg, -25 mm Hg, -35 mm Hg, and -45 mm Hg) were studied in humans (n = 10). The LBNP's were applied in a random order (three per session) for 20 min, with 15 min between each LBNP. Leg blood flow, cardiac output (Q), stroke volume (SV) and estimated lung blood volume were significantly reduced at -15 mm Hg. Increasing LBNP to -35 mm Hg did not result in further changes. When the LBNP was increased to -45 mm Hg, Q and SV were lower than comparable values at -15 mm Hg. Heart rate was unchanged up to -25 mm Hg, after which it increased proportionally to the LBNP. Systolic blood pressure was maintained throughout. Diastolic blood pressure was unchanged below -45 mm Hg, but was significantly elevated at -45 mm Hg. Mean arterial pressure was maintained up to LBNP's of -35 mm Hg by increased vascular resistance, in spite of reduced thoracic blood volume, as indicated by reduced central venous pressure and Q. Greater levels of LBNP were outside the physiological adjustment range and blood pressure dropped progressively.

Local pulmonary blood flow: control and gas exchange.

We studied the local response of the pulmonary vasculature to combined changes in alveolar PO2 and PCO2 in the right apical lobe (RAL) of six conscious sheep. That lobe inspired an O2-CO2-N2 mixture adjusted to produce one of 12 alveolar gas compositions: end-tidal PCO2 (PETCO2) of 40, 50, and 60 Torr, each coupled with end-tidal PO2 (PETO2) of 100, 75, 50, and 25 Torr. In addition, at each of the four PETO2, the inspired CO2 was set to 0 and PETCO2 was allowed to vary as RAL perfusion changed. The remainder of the lung, which served as control (CL) inspired air. Fraction of the total pulmonary blood flow going to the RAL (%QRAL) was obtained by comparing the methane elimination from the RAL to that of the whole lung, and expressed as a percentage of that fraction at PETCO2 = 40, PETO2 = 100. Cardiac output, pulmonary vascular pressures, and CL gas tensions were unaffected or only minimally affected by changes in RAL gas composition. A drop in PO2 from 100 to 50 Torr decreased local blood flow by 60% in normocapnia and by 66% at a PCO2 of 60. At all levels of oxygenation, an increase in PCO2 from 40 to 60 reduced QRAL by nearly 50%. With these stimulus-response data, we developed a model of gas exchange, which takes into account the effects of test segment size on blood flow diversion. This model predicts that: (1) when the ventilation to one compartment of a two compartment lung is progressively decreased, PAO2 remains above 60 Torr for up to 60% reductions in alveolar ventilation, irrespective of compartment size; (2) the decrease in PAO2 that occurs at altitude is accompanied by a drop in PACO2 that limits the decrease in conductance and minimizes the pulmonary hypertension; and (3) as we stand, local blood flow control by the alveolar gas tensions halves the alveolar-arterial PO2 and PCO2 differences imposed by gravity.

Prolonged lobar hypoxia in vivo enhances the responsivity of isolated pulmonary veins to hypoxia.

The hypoxic response of pulmonary vessels isolated from eight sheep whose right apical lobes (RAL) had inspired 100% N2 for 20 h was studied. The RAL of these conscious sheep inspired hypoxic gas and the remainder of the lung inspired air. During hypoxia, RAL perfusion was 33 +/- 3% of its air value, carotid arterial PO2 averaged 86 +/- 3 mm Hg and pulmonary perfusion pressure was not significantly different from the initial control period when the RAL inspired air. At the end of the hypoxic exposure, the sheep were killed, and pulmonary artery and vein rings (0.5 to 2 mm inner diameter) were isolated from both the RAL and the right cardiac lobe, which served as the control lobe (CL). Arteries from the RAL and CL did not contract in response to 6% O2/6% CO2/88% N2 (hypoxia). In contrast, RAL veins did contract vigorously in response to hypoxia, whereas CL veins did not contract or contracted only minimally. Rubbing of the endothelium or prior incubation of RAL veins with catalase (1,200 units/ml), indomethacin (10(-5) M), or the thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor antagonist, SQ 29,548 (3 X 10(-6) M) each significantly reduced the response to hypoxia. RAL veins were also found to be more reactive than CL veins to the prostaglandin endoperoxide analogue U46619. We conclude that prolonged lobar hypoxia in vivo increases the responsivity of isolated pulmonary veins to hypoxia. These contractions may result from an increase in reactive O2 species, which in turn modify production of, metabolism of, and/or tissue responsivity to TxA2/PGH2.

Pulmonary hypoxic vasoconstriction: how strong? How fast?

We have developed a minimally invasive technique for studying regional blood flow in conscious sheep, bypassing the complications of open-chest surgery, flow probes and tracer infusion. We quantitate regional perfusion continuously on the basis of regional clearance of methane (methane is produced in the sheep rumen, enters the circulation and is eliminated nearly completely (greater than 95%) in the lung). Tracheal intubation with a dual-lumen catheter isolates the gas exchange of the right apical lobe (RAL; less than 15% of the lung) from that of the remainder of the lung, which serves as a control (CL). We measure RAL and CL methane elimination by entraining expirates in constant flows, sampled continuously for methane. Results obtained with this technique and from regional oxygen uptake are in excellent agreement. We have found that hypoxic vasoconstriction is far more potent and stable during eucapnic hypoxia than during hypocapnic hypoxia. The time course of the vasoconstriction suggests that many of the data in the literature may have been obtained prior to steady state.

Pulmonary circulation and systemic circulation: similar problems, different solutions.

Both the systemic and the pulmonary circulations respond to local hypoxia in the appropriate manner, the former by vasodilating, thereby providing more oxygen, and the latter by constricting and rerouting blood flow to areas where more O2 is available. In either case, changes in local conductance affect total conductance, and through that variable, the perfusing pressure; as a result, the effects of local vasomotion should be reduced. In the systemic circulation, arterial pressure can be prevented from falling by two important mechanisms: vasoconstriction of other vascular beds, and an increase in cardiac output. There are no similar means for protecting pulmonary arterial pressure against a rise when vessels in hypoxic areas contract; the only defense is provided by passive expansion of the vascular bed. Thus, in the lung regional circulatory readjustments conflict with the need to maintain a reasonably low pulmonary arterial pressure and local regulation (and maintenance of arterial oxygenation) may be subordinate to prevention of pulmonary hypertension.

Biomedical support of man in space.

In its broadest sense, biomedical support of man in space must not be limited to assisting spacecraft crew during the mission; such support should also ensure that flight personnel be able to perform properly during landing and after leaving the craft. Man has developed mechanisms that allow him to cope with specific stresses in his normal habitat; there is indisputable evidence that, in some cases, the space environment, by relieving these stresses, has also allowed the adaptive mechanisms to lapse, causing serious problems after re-entry. Inflight biomedical support must therefore include means to simulate some of the normal stresses of the Earth environment. In the area of cardiovascular performance, we have come to rely heavily on complex feedback mechanisms to cope with two stresses, often combined: postural changes, which alter the body axis along which gravitational acceleration acts, and physical exercise, which increases the total load on the system. Unless the appropriate responses are reinforced continuously during flight, crew members may be incapacitated upon return. The first step in the support process must be a study of the way in which changes in g, even of short duration, affect these responses. In particular we should learn more about effects of g on the "on" and "off" dynamics, using a variety of approaches: increased acceleration on one hand at recumbency, immersion, lower body positive pressure, and other means of simulating some of the effects of low g, on the other. Once we understand this, we will have to determine the minimal exposure dose required to maintain the response mechanisms. Finally, we shall have to design stresses that simulate Earth environment and can be imposed in the space vehicle. Some of the information is already at hand; we know that several aspects of the response to exercise are affected by posture. Results from a current series of studies on the kinetics of tilt and on the dynamics of readjustment to exercise in different postures will be presented and discussed.

Gravity-induced hyperventilation is caused by a reduced brain perfusion.

The suggestion that hyperventilation caused by increased gravity is mediated by a decrease in brain perfusion has led us to propose a mathematical model based on: (1) the CO2 balance equation for the respiratory center (RC), and (2) the relationship between RC blood flow (QRC), foot-to-head acceleration (Gz) and PRCCO2, namely, QRC = [1 - a(Gz - 1)](b X PRCCO2 + c), where the coefficients a, b and c can be calculated from data in the literature. QRC is significantly affected by + GZ only at high PaCO2. The model can be used to calculate oxygen pressure in the RC; the numbers so obtained are in good agreement with measurements of jugular vein PO2 obtained by others.

Acid-base status immediately following rapid changes of alveolar gas composition in awake dogs.

To study the interrelationship between blood O2, CO2, and acid-base status during rapid changes of alveolar gas composition unanesthetized dogs were made to inhale high CO2 gas mixtures following air breathing or to rebreathe high CO2 and O2 mixtures following hypoxia. Before and immediately after each change in alveolar gases, sequential blood samples were taken from the carotid artery for measurement of pH, PCO2 and PO2. In the experiments at normoxia the calculated base excess (BE) decreased by about 0.7 mmol/L after 10 sec and then returned to baseline level. A smaller decrease (averaging 0.4 mmol/L) was found with hyperoxia following hypoxia. The changes in BE can be attributed to bicarbonate (or H+) exchange between blood and tissue. Lung tissue is probably responsible for the rapid initial change in BE.

Blood-gas transport in awake rabbits exposed to normobaric hyperoxia.

The time course and terminal effects of normobaric oxygen exposure on the gas transport chain were studied in awake, catheterized rabbits exposed to air (n = 8) for 96 h or 100% O2 (n = 10) until death. O2-breathing animals survived 60.2 (+/- 13.5 SD) h. Pao2 increased and was maintained until within 4.9 (+/- 1.4) h of death. Mixed venous O2 tension rose sharply but transiently upon O2 exposure. In most animals, death followed a precipitous fall in PaCO2, a moderate rise in PaCO2, and a drop in pHa. The terminal acidosis was largely metabolic, nearly half due to lactic acidemia. There were transient appearances of metabolic acids early in the exposures before the PaCO2 decreased. Furthermore, in the last hours, fixed acids appeared when PaCO2 was unchanged or slightly decreased, but before the animal became hypoxemic. Metabolic acidosis without arterial hypoxemia could result from cardiac insufficiency, or alterations in metabolism, or in patterns of distribution of blood flow within peripheral beds. Thus, normobaric O2 exposure has precipitous and terminal effects on pulmonary gas exchange, but arterial hypoxemia is not necessarily the cause of death.

Effect of water immersion on cardiopulmonary physiology at high gravity (+Gz).

We compared the cardiopulmonary physiology of eight subjects exposed to 1, 2, and 3 Gz during immersion (35 degrees C) to the heart level with control dry rides. Immersion should almost cancel the effects of gravity on systemic circulation and should leave the lung alone to gravitational influence. During steady-state breathing we measured ventilation, O2 consumption (VO2), CO2 production, end-tidal PCO2 (PACO2), and heart frequency (fH). Using CO2 rebreathing techniques, we measured cardiac output, functional residual capacity, equivalent lung tissue volume, and mixed venous O2 content, and we calculated arterial PCO2 (PaCO2). As Gz increased, ventilation, fH, and VO2 rose markedly, and PACO2 and PaCO2 decreased greatly in dry ride, but during immersion these variables changed very little in the same direction. Functional residual capacity was lower during immersion and decreased in both the dry and immersed states as Gz increased, probably reflecting closure effects. Cardiac output decreased as Gz increased in dry rides and was elevated and unaffected by Gz during immersion. We conclude that most of the changes we observed during acceleration are due to the effect on the systemic circulation, rather than to the effect on the lung itself.

Influence of breathing frequency and tidal volume on cardiac output.

The aim of our experiment was to investigate the influence of increasing either breathing frequency or tidal volume on cardiac output (Q), in normocapnia. We measured Q with a CO2 rebreathing method in 6 men and 6 women in the sitting and the supine position, imposing different breathing patterns: in one set of experiments tidal volume was kept constant at 1 L while breathing frequency was randomly changed between 20, 30 and 40 breaths/min; in another breathing frequency was kept constant at 30 breaths/min while tidal volume was randomly altered between 1, 1.5 and 2 L. Switching from open circuit breathing to rebreathing (for measurement of Q) required no change in breathing pattern. From the beginning, CO2 was added to the inspired gas to maintain end-tidal FCO2 at 0.054, so as to obtain steady state conditions throughout the measurements. Q rose significantly when tidal volume was increased (938 ml/L rise in tidal volume when sitting, and 743 ml/L when supine). Breathing frequency had an insignificant effect (213 ml/10 breaths frequency increase when sitting and 142 ml/10 breaths when supine). The greater influence of ventilation on Q when sitting than when supine is best explained by the fact that in the latter position venous return is already high. There are no demonstrable differences in this effect between males and females.

A fundamental problem in determining functional residual capacity or residual volume.

To measure a lung volume that is not directly accessible, one often follows dilution of a single-gas tracer, present initially only in the lung or in a rebreathing bag. The final volume available to the tracer is assumed to be the sum of the two initial components. Since O2 is taken up and CO2 is eliminated during the few breaths required for mixing, the total volume changes. The error in lung volume due to this volume change can exceed 10%. In this paper we 1) present theoretical and experimental data to demonstrate the effect of CO2 and O2 exchange, 2) introduce a general equation, based on N2 and Ar, which allows one to circumvent the problems created by these fluxes, and 3) show the pitfall of the back-extrapolation approach for a single tracer.

Ventilation and CO2 response during +Gz acceleration.

During foot-to-head acceleration (+Gz) ventilation increases despite a drop in alveolar PCO2. In order to investigate the underlying mechanisms, we measured ventilation (VE), VO2, VCO2 and PACO2, cardiac output (Q) and mixed venous CO2 concentration (CVCO2) using non-invasive techniques in 5 subjects breathing either air or a gas mixture containing 5% CO2 at +1, +2 and +3 Gz in a human centrifuge. Arterial PCO2 was calculated from Fick's equation, using CVCO2, Q and VCO2. VE increased from 8.7 to 18.0 L/min during air breathing and from 19.6 to 36.9 L/min during CO2 breathing at +1 and +3 Gz, respectively. The corresponding values for PACO2 are 37.9 vs 26.9 Torr and 47.8 vs 46.4 Torr. Q dropped from 5.9 to 4.8 L/min during air breathing and remained the same during CO2 breathing (6.7 vs 6.5 L/min). As the decrease of PaCO2 almost paralleled that of PACO2, the arterio-alveolar CO2 difference increased only slightly. The CO2 response curve shifts gradually to the left with an increase in +Gz, a fact that does not support the hypothesis that foot-to-head acceleration increases CO2 sensitivity.

Gas exchange in tidally ventilated and non-steadily perfused lung model.

We studied the effect of cyclic lung perfusion - fast cycle in synchrony with heart beats and slow cycle in synchrony with ventilation - on gas exchange in a lung model. There was almost no effect in the fast cycle. In a homogeneous single-lung unit, arterial PO2 increased, and the (A - a)DO2 decreased (by approximately 0.5 Torr), as the amplitude of the slow cyclic lung perfusion (TIP) increased. The calculated (A - a)DO2 and (a - A)DCO2 were negative. Maximal PaO2 was found when peak lung perfusion was delayed with respect to ventilation by 0.2 of a cycle. In a non-homogeneous nine-unit lung, cyclic lung perfusion caused an increase in PaO2 and a decrease in (A - a)DO2 by 2 Torr as compared to steady perfusion. No apparent negative (A - a)DO2 was found, but apparent negative (a - A)DCO2 was calculated at no pulmonary shunt and also with 5% shunt. The correlation of cyclic lung perfusion to the reduced (A - a)DO2 in dense-gas breathing - where large swings of pleural pressure are expected - and its effect on the diffusion capacity of the lung are discussed. Non-steady perfusion of the lung as caused by ventilatory movements expanded our understanding of gas exchange and shed some light on a few controversial experimental findings, such as the negative (a - A)DCO2, the decreased (A - a)DO2 while breathing dense gas, and the effects of gas density on diffusion capacity of the lung.

Cardiovascular responses to hemodilution and controlled hypotension in the dog.

Cardiovascular responses to acute hemodilution and controlled hypotension were studied in mongrel dogs anesthetized with halothane and paralyzed with pancuronium. Regional blood flows were determined by microsphere injections. Hemodilution to an hematocrit of 23% was produced by removal of whole blood and simultaneous infusion of Ringer's lactate solution. Subsequently, hypotension to a mean arterial pressure of 55 mmHg was produced for 90 min by intravenous infusion of trimethaphan. The hypotension resulted entirely from a 55% decrease in total peripheral resistance. Thirty minutes after initiation of controlled hypotension, there were significant increases in blood flow to the brain, liver, skeletal muscles, and diaphragm. However, at 30 min, calculated oxygen delivery had decreased to brain (-16%), renal cortex (-51%), heart (-45%), and retina (-44%). By 90 min, retinal, adrenal, and renal cortical blood flows were decreased significantly relative to control, and cerebral blood flows had returned to control levels. Absence of changes in acid-base status during the period of hemodilution and hypotension may indicate that whole body oxygen delivery was maintained at adequate levels. However, major decreases in calculated oxygen delivery after 90 min to critical tissue beds such as renal cortex (-67%) and retina (-78%) indicate that extension of the procedure past 30 min may involve risks that are not warranted by the benefits.