Effects of hypercarbia on arterial and alveolar oxygen tensions in a model of gram-negative pneumonia

Inspired CO2 causing changes from hypo- to normocapnia has previously been shown to improve arterial O2 tension (PaO2) and to reduce alveolar-arterial O2 difference. The effect of further increases in inspired CO2 to hypercarbic levels has not been studied in inflammatory lung disease. Three days after induction of sublobar Pseudomonas pneumonia, Suffolk sheep were anesthetized and ventilated with a fixed-volume ventilator. After 2.5 h, CO2 was added to the inspired gas to raise arterial CO2 tension (PaCO2) to 60-65 Torr. Four hours later the CO2 was withdrawn and ventilation continued for an additional 2 h. Constant minute ventilation and inspired O2 fraction were maintained. Regional lung perfusion was measured by injection of radioactive microspheres. With the administration of CO2, PaO2 increased significantly from 65.5 to 77.5 Torr as did alveolar O2 tension (from 109.7 to 120.0 Torr) with no significant change in alveolar-arterial O2 difference. There were no significant changes in cardiac output, shunt fraction, O2 uptake, O2 delivery, respiratory quotient, or distribution of regional lung perfusion. We conclude that the increases in alveolar O2 tension and PaO2 with the added CO2 resulted from improved alveolar ventilation.     

Chronic stable asthma and the normal arterial pressure of carbon dioxide in hypoxia.

Arterial blood-gas tensions, pH, and peak expiratory flow rate were measured in 29 patients with chronic asthma in a stable state. The hypoxia in these patients was found to be comparable with the hypoxia seen in normal subjects at high altitude in its effects on arterial pressure of carbon dioxide (PaCO2). These results suggest that in patients with asthma the PaCO2 taken as normal should be related to the arterial oxygen tension. Any increase in the observed value compared with this predicted value indicates impaired respiratory control. This may well help in assessing the patients at greatest risk during an attack of asthma.     

Effect of increased gas density on pulmonary gas exchange in man.

Pulmonary gas exchange was measured in seven resting supine subjects breathing air or a dense gas mixture containing 21% O2 in sulfur hexafluoride (SF6). The mean value of the alveolar-arterial oxygen difference (AaDO2) decreased from 12.4 on air to 7.0 on SF6 (P less than 0.01), and increased again to 13.4 when air breathing resumed (P less than 0.01). No differences occurred between gas mixtures for O2 consumption, respiratory quotient, minute ventilation, breathing frequency, heart rate, or blood pressure, and the improved oxygen transfer could not be attributed to changes in cardiac output or mixed venous oxygen content in the one subject in which they were measured. These results are best explained by an altered distribution of ventilation during dense gas breathing, so that the ventilation-perfusion ratio (VA/Q) variance was reduced. Of several considered mechanisms, we favor one in which SF6 promotes cardiogenic gas mixing between peripheral parallel units having different alveolar gas concentrations. This mechanism allows for observed increases in arterial carbon dioxide tension and dead space-to-tidal volume ratio during dense gas breathing, and suggests that intraregional VA/Q variance accounts for at least one-half of the resting AaDO2 in healthy supine young men.     

Alveolar dead space does not affect indirect Fick cardiac output determinations

We examined the influence of three variables (different breathing circuits, breath selected for analysis, and alveolar dead space ventilation) on the accuracy of noninvasive cardiac output determinations with the Fick CO2 (indirect) equation. We compared noninvasive determinations with invasive thermodilution measurements over a wide range of cardiac outputs in 17 2-mo-old pigs anesthetized with halothane and nitrous oxide and paralyzed with either pancuronium or d-tubocurare. We found that rebreathing and nonrebreathing circuits provide accurate cardiac output determinations and that the optimal breath for analysis with either the rebreathing or nonrebreathing technique appears to depend on the cardiac output. When alveolar dead space was increased by using positional changes and the intracardiac administration of glass beads, there was still a good correlation between noninvasive and invasive cardiac output determinations. We conclude that both rebreathing and nonrebreathing techniques of indirect Fick cardiac output determinations correlate well with thermodilution measures over a wide range of cardiac outputs and alveolar dead space/tidal volume fractions.     

Negative arterial-mixed expired PC02 gradient during acute and chronic hypercapnia.

In resting conscious dogs physiological dead space was calculated using the Bohr equation and measurements of arterial and mixed expired carbon dioxide tension. Whenever dogs inhaled carbon dioxide mixtures (5-10%) that had normal or low oxygen concentrations, the calculated dead space became negative. This paradox was based on the fact that the mixed expired carbon dioxide tension in resting hypercapnic dogs. Under these circumstances carbon dioxide was produced from the lung as measured by gas analyses and blood analyses. By the lung as measured by gas analyses and blood analyses. By reasoning this implies that "alveolar" carbon dioxide tension was higher than pulmonary venous carbon dioxide tension. The negative carbon dioxide gradient persisted at 14 days of chronic hypercapnia and reverted to normal within 10 min of breathing air after chronic hypercapnia. These findings suggest that the exchange of carbon dioxide in the lung cannot be explained solely on the basis of passive diffusion.     

Respiratory Insufficiency in Acute Myocardial Infarction

Arterial blood gases and pH were assessed in 115 patients who had suffered a myocardial infarction, with or without complicating cardiogenic shock or cardiac standstill. In 11 of the 78 uncomplicated cases and in 16 of the 37 complicated cases, the arterial O₂ tension was much lower than would be expected on the basis of a three-fold drop in cardiac output, indicating considerable right to left shunting. The death rate in the patients with uncomplicated myocardial infarction was 32% and that of the complicated cases 65%. In both groups it was greatest when the arterial pH was low, indicating that correction of the acidosis is essential. In many instances administration of 100% oxygen is inadequate to restore the oxygen tension to normal levels, and controlled ventilation may be necessary to maintain adequate alveolar ventilation. The findings indicate the necessity for repeated assessment of the arterial blood gas tensions and pH in any patient who has suffered a myocardial infarction. If the management of such patients is designed to provide adequate oxygenation, to maintain adequate alveolar ventilation and to correct the acid-base disturbances, the patient may be tided over the stage of “cardiac pump failure”.     

Hyperventilation in ponies at the onset of and during steady-state exercise

We studied blood gases in ponies to assess the relationship of alveolar ventilation (VA) to pulmonary CO2 delivery during moderate treadmill exercise. In normal ponies for 1.8, 3, or 6 mph, respectively, partial pressure of CO2 in arterial blood (PaCO2) decreased maximally by 3.1, 4.4, and 5.7 Torr at 30-90 s of exercise and remained below rest by 1.4, 2.3, and 4.5 Torr during steady-state (4-8 min) exercise (P less than 0.01). Partial pressure of O2 in arterial blood (PaO2) and arterial pH, (pHa) also reflected hyperventilation. Mixed venus CO2 partial pressure (PVCO2) decreased 2.3 and 2.9 Torr by 30 s for 3 and 6 mph, respectively (P less than 0.05). In work transitions either from 1.8 to 6 mph or from 6 mph to 1.8 mph, respectively, PaCO2 either decreased 3.8 Torr or increased 3.3 Torr by 45 s of the second work load (P less than 0.01). During exercise in acute (2-4 wk) carotid body denervated (CBD) ponies at 1.8, 3, or 6 mph, respectively, PaCO2 decreased maximally below rest by 9.0, 7.6, and 13.2 Torr at 30-45 s of exercise and remained below rest by 1.3, 2.3, and 7.8 Torr during steady-state (4-8 min) exercise (P less than 0.1). In the chronic (1-2 yr) CBD ponies, the hypocapnia was generally greater than normal but less than in the acute CBD ponies. We conclude that in the pony 1) VA is not tightly matched to pulmonary CO2 delivery during exercise, particularly during transitional states, 2) the exercise hyperpnea is not mediated by PaCO2 or PVCO2, and 3) during transitional states in the normal pony, the carotid bodies attenuate VA drive thereby reducing arterial hypocapnia.     

Respiratory effects of the Jarvik-7 artificial heart

In five anesthetized patients with a Jarvik-7 artificial heart, pulmonary volume displacements generated by cardiogenic oscillations were measured using an indirect spirometric method. Consequences on gas exchange were also evaluated during a 15-min period of apnea by use of a tracheal insufflation of pure O2 at a constant flow rate of 20 l/min. The Jarvik-7 artificial heart generated a mean pulmonary volume displacement of 105 +/- 29 (SD) ml/heart beat. After 15 min of apnea, arterial PCO2 (PaCO2) significantly increased from 29 +/- 5 to 47 +/- 6 (SD) Torr. PaCO2 increased by 0.8 Torr/min from the 5th to the 15th min of apnea. Mean arterial PO2, mean pulmonary shunt, mean O2 consumption, and mean metabolic production of CO2 did not change significantly during the apnea period. Because cardiac output was kept constant during the study, O2 transport was adequately maintained throughout the apnea period. In patient 1, where the period of apnea was continued for 60 min, PaCO2 progressively increased until the 45th min and then remained stable at 61 Torr during the last 15 min of apnea. This "plateau" corresponded to an alveolar ventilation of 3,907 ml/min, representing 69% of the alveolar ventilation calculated during conventional mechanical ventilation. In conclusion, the Jarvik-7 artificial heart provides a potent respiratory support through the cardiogenic oscillations it generates.     

Effect of high-intensity exercise on the VE-VCO2 relationship

The intrinsic relationship between ventilation (VE) and carbon dioxide output (VCO2) is described by the modified alveolar ventilation equation VE = VCO2 k/PaCO2(1-VD/VT) where PaCO2 is the partial pressure of CO2 in the arterial blood and VD/VT is the dead space fraction of the tidal volume. Previous investigators have reported that high-intensity exercise uncouples VE from VCO2; however, they did not measure the PaCO2 and VD/VT components of the overall relationship. In an attempt to provide a more complete analysis of the effects of high-intensity exercise on the VE-VCO2 relationship, we undertook an investigation where five subjects volunteered to perform three steady-state tests (SS1, SS2, SS3) at 60 W. One week after SS1 each subject was required to perform repeated 1-min bouts of exercise corresponding to a work rate of approximately 140% of maximal oxygen uptake (VO2max). Two and 24 h later the subjects performed SS2 and SS3, respectively. This exercise intervention caused PaCO2 during SS2 and SS3 to be regulated (P less than 0.01) approximately 4 Torr below the control (SS1) value of 38.8 Torr. Additionally, significant alterations were noted for VCO2 with corresponding values of 1.15 (SS1), 1.10 (SS2), and 1.04 (SS3) l/min. No changes were noted in either VD/VT or VE. In summary, it seems reasonable to suggest that the disproportionate increase in VE with respect to VCO2 noted in earlier work does not reflect an uncoupling. Rather the slope of the VE-VCO2 relationship is increased in a predictable manner as described by the modified alveolar ventilation equation.     

Non-invasive mechanical ventilation for acute respiratory failure.

The value of mechanical ventilation using intermittent positive pressure ventilation delivered non-invasively by nasal mask was assessed in six patients with life threatening exacerbations of chronic respiratory disease. Median (range) arterial oxygen and carbon dioxide tensions were 4.4 (3.5-7.2) kPa and 8.7 (5.5-10.9) kPa respectively, with four patients breathing air and two controlled concentrations of oxygen. The arterial oxygen tension increased with mechanical ventilation to a median (range) of 8.7 (8.0-12.6) kPa and the carbon dioxide tension fell to 8.2 (6.5-9.2) kPa. Four patients discharged after a median of 10 (8-17) days in hospital were well five to 22 months later. One died at four days of worsening sputum retention and another after five weeks using the ventilator for 12-16 hours each day while awaiting heart-lung transplantation. This technique of mechanical ventilation avoids endotracheal intubation and can be used intermittently. Hypercapnic respiratory failure can be relieved in patients with either restrictive or obstructive lung disease in whom controlled oxygen treatment results in unacceptable hypercapnia. Respiratory assistance can be tailored to individual need and undertaken without conventional intensive care facilities.     

Reflex control of vascular capacitance during hypoxia, hypercapnia, or hypoxic hypercapnia

We tested the hypothesis that the changes in venous tone induced by changes in arterial blood oxygen or carbon dioxide require intact cardiovascular reflexes. Mongrel dogs were anesthetized with sodium pentobarbital and paralyzed with veruronium bromide. Cardiac output and central blood volume were measured by indocyanine green dilution. Mean circulatory filling pressure, an index of venous tone at constant blood volume, was estimated from the central venous pressure during transient electrical fibrillation of the heart. With intact reflexes, hypoxia (arterial PaO2 = 38 mmHg), hypercapnia (PaCO2 = 72 mmHg), or hypoxic hypercapnia (PaO2 = 41; PaCO2 = 69 mmHg) (1 mmHg = 133.32 Pa) significantly increased the mean circulatory filling pressure and cardiac output. Hypoxia, but not normoxic hypercapnia, increased the mean systemic arterial pressure and maintained the control level of total peripheral resistance. With reflexes blocked with hexamethonium and atropine, systemic arterial pressure supported with a constant infusion of norepinephrine, and the mean circulatory filling pressure restored toward control with 5 mL/kg blood, each experimental gas mixture caused a decrease in total peripheral resistance and arterial pressure, while the mean circulatory filling pressure and cardiac output were unchanged or increased slightly. We conclude that hypoxia, hypercapnia, and hypoxic hypercapnia have little direct influence on vascular capacitance, but with reflexes intact, there is a significant reflex increase in mean circulatory filling pressure.     

Ventilatory and blood gas dynamics at onset and offset of exercise in the pony

The purpose of these experiments was to examine the temporal pattern of arterial carbon dioxide tension (PaCO2) to assess the relationship between alveolar ventilation (VA) and CO2 return to the lung at the onset and offset of submaximal treadmill exercise. Five healthy ponies exercised for 8 min at two work rates: 50 m/min 6% grade and 70 m/min 12% grade. PaCO2 decreased (P less than 0.05) below resting values within 1 min after commencement of exercise at both work rates and reached a nadir at 90 s. PaCO2 decreased maximally by 2.5 and 3.5 Torr at the low and moderate rate, respectively. After the nadir, PaCO2 increased across time during both work rates and reached values that were not significantly different (P greater than 0.05) from rest at minute 4 of exercise. Partial pressure of O2 in arterial blood and arterial pH reflected hyperventilation during the first 3 min of exercise. At the termination of exercise PaCO2 increased (1.5 Torr) above rest (P less than 0.05), reaching a zenith at 2-3 min of recovery. These data suggest that VA and CO2 flow to the lung are not tightly matched at the onset and offset of exercise in the pony and thus challenges the traditional concept of blood gas homeostasis during muscular exercise.     

Combination of constant-flow and continuous positive-pressure ventilation in canine pulmonary edema

Constant-flow ventilation (CFV) maintains alveolar ventilation without tidal excursion in dogs with normal lungs, but this ventilatory mode requires high CFV and bronchoscopic guidance for effective subcarinal placement of two inflow catheters. We designed a circuit that combines CFV with continuous positive-pressure ventilation (CPPV; CFV-CPPV), which negates the need for bronchoscopic positioning of CFV cannula, and tested this system in seven dogs having oleic acid-induced pulmonary edema. Addition of positive end-expiratory pressure (PEEP, 10 cmH2O) reduced venous admixture from 44 +/- 17 to 10.4 +/- 5.4% and kept arterial CO2 tension (PaCO2) normal. With the innovative CFV-CPPV circuit at the same PEEP and respiratory rate (RR), we were able to reduce tidal volume (VT) from 437 +/- 28 to 184 +/- 18 ml (P less than 0.001) and elastic end-inspiratory pressures (PEI) from 25.6 +/- 4.6 to 17.7 +/- 2.8 cmH2O (P less than 0.001) without adverse effects on cardiac output or pulmonary exchange of O2 or CO2; indeed, PaCO2 remained at 35 +/- 4 Torr even though CFV was delivered above the carina and at lower (1.6 l.kg-1.min-1) flows than usually required to maintain eucapnia during CFV alone. At the same PEEP and RR, reduction of VT in the CPPV mode without CFV resulted in CO2 retention (PaCO2 59 +/- 8 Torr). We conclude that CFV-CPPV allows CFV to effectively mix alveolar and dead spaces by a small bulk flow bypassing the zone of increased resistance to gas mixing, thereby allowing reduction of the CFV rate, VT, and PEI for adequate gas exchange.     

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.     

Arterial-alveolar CO2 equilibration in exercising dogs during prolonged rebreathing

Arterial-alveolar equilibration of CO2 during exercise was studied by normoxic CO2 rebreathing in six dogs prepared with a chronic tracheostomy and exteriorized carotid loop and trained to run on a treadmill. In 153 simultaneous measurements of PCO2 in arterial blood (PaCO2) and end-tidal gas (PE'CO2) obtained in 46 rebreathing periods at three levels of mild-to-moderate steady-state exercise, the mean PCO2 difference (PaCO2-PE'CO2) was -1.0 +/- 1.0 (SD) Torr and was not related to O2 uptake or to the level of PaCO2 (30-68 Torr). The small negative PaCO2-PE'CO2 is attributed to the lung-to-carotid artery transit time delay which must be taken into account when both PaCO2 and PE'CO2 are continuously rising during rebreathing (average rate 0.22 Torr/s). Assuming that blood-gas equilibrium for CO2 was complete, a lung-to-carotid artery circulation time of 4.6 s accounts for the observed uncorrected PaCO2-PE'CO2 of -1.0 Torr. The results are interpreted to indicate that in rebreathing equilibrium PCO2 in arterial blood and alveolar gas are essentially identical. This conclusion is at variance with previous studies in exercising humans during rebreathing but is in full agreement with our recent findings in resting dogs.     

Effects of naloxone on pethidine-induced neonatal depression. Part I--Intravenous naloxone.

Infants whose mothers had had pethidine during labour were given either naloxone 40 microgram or isotonic saline administered intravenously double-blind within one minute of birth. Peak alveolar carbon dioxide tension, carbon dioxide excretion, alveolar ventilation, feeding behaviour, and habituation to a specific sound stimulus were measured regularly up to 48 hours after birth. Alveolar carbon dioxide tension was significantly lower and alveolar ventilation significantly higher half an hour after birth in the naloxone-treated group than in the saline-treated group, but these differences between the groups were not significant at any other time, and there were no significant differences in sucking frequency or pressure, milk consumption, or habituation to the auditory stimulus.     

Regulation of arterial PCO2 during intravenous CO2 loading.

Increased CO2 flow to the lung produced by increasing cardiac output (with constant PVCO2) results in hyperpnea with arterial PCO2 maintained at its control value (J. Appl. Physiol. 36: 457, 1974). To study if arterial PCO2 could be similarly regulated when CO2 flow was elevated by increasing PVCO2 (without changing cardiac output), we produced graded increases in PVCO2 (up to a mean of 69 mmHg) using an extracorporeal gas exchanger in five chloralose-urethan-anesthetized dogs. CO2 output increased up to fourfold. Ventilation increased in proportion to the additional CO2 flow to the lung with consequent regulation of arterial PCO2 at its control value. Comparable increases in VE produced by "conventional" airway loading resulted in arterial hypercapnia. The resulting CO2 response curve was similar to that found in unanesthetized dogs. We conclude that intravenous delivery of CO2 to the lung results in infinite "sensitivity" when computed as Delta VE/Delta paco2. These results provide evidence for a CO2-linked hyperpnea which is not mediated by measurable increases in mean arterial PCO2.     

Haemodynamic effects of respiratory alkalosis independent of changes in airway pressure in anaesthetized newborn dogs

We have recently reported a decrease in cardiac output in newborn dogs during respiratory alkalosis which is independent of changes in airway pressure. The present study was designed to characterize the mechanism responsible for this reduction in cardiac output. Twelve newborn coonhounds were anaesthetized with pentobarbital, paralyzed with pancuronium and hyperventilated to an arterial carbon dioxide tension (PaCO2) of 20 torr. Subsequent changes in PaCO2 were achieved by altering the FiCO2. Measurements were made after 30 min at either 40 or 20 torr PaCO2. The sequence of PaCO2 levels was randomized. Compared to normocarbia, respiratory alkalosis resulted in significantly decreased cardiac output (279 +/- 16 to 222 +/- 10 ml/min per kg, mean +/- SEM, P less than 0.001), stroke volume (1.60 +/- 0.10 to 1.24 +/- 0.06 ml/kg; P less than 0.001), maximum left ventricular dP/dt (1629 +/- 108 to 1406 +/- 79 mmHg/s, P less than 0.01) and left ventricular end diastolic pressure (3.9 +/- 0.4 to 2.9 +/- 0.3 mmHg; P less than 0.001). The decrease in cardiac output during respiratory alkalosis is manifest through a decrease in stroke volume, which is due, at least in part, to the decrease in left ventricular end diastolic pressure. The decrease in maximum left ventricular dP/dt is likely a reflection of the decrease in preload, however, a change in myocardial contractility cannot be excluded. We speculate the decrease in filling pressure may be due to an increase in venous capacitance.     

Effects of hyperventilation on pulmonary blood flow and recirculation time of humans

We used direct invasive techniques to measure the effects of hyperventilation on the pulmonary blood flow (Q) and on recirculation time of helium and of carbon dioxide in humans. The subjects hyperventilated with a tidal volume of 1.5 liters (BTPS) and a frequency of 20 or 30 breaths/min. There was no significant change in Q from control at either level of hyperventilation. Helium first appeared in the pulmonary artery within 12 s from the onset of hyperventilation and increased by approximately 0.7% of its equilibrium arterial value per second at both levels of hyperventilation. In contrast, the PVCO2 remained at base-line level until 43 s from the onset of hyperventilation. We conclude that hyperventilation at 30 or 45 l/min with constant tidal volume does not significantly affect the value of Q and that the amount of recirculation of the two gases does not result in underestimation of Q when this variable is measured by indirect respiratory rebreathing techniques.     

Blood-gas equilibration of CO2 and O2 in lungs of awake dogs during prolonged rebreathing

To reinvestigate the blood-gas CO2 equilibrium in lungs, rebreathing experiments were performed in five unanesthetized dogs prepared with a chronic tracheostomy and an exteriorized carotid loop. The rebreathing bag was initially filled with a gas mixture containing 6-8% CO2, 12, 21, or 39% O2, and 1% He in N2. During 4-6 min of rebreathing PO2 in the bag was kept constant by a controlled supply of O2 while PCO2 rose steadily from approximately 40 to 75 Torr. Spot samples of arterial blood were taken from the carotid loop; their PCO2 and PO2 were measured by electrodes and compared with the simultaneous values of end-tidal gas read from a mass spectrometer record. The mean end-tidal-to-arterial PO2 differences averaging 16, 4, and 0 Torr with bag PO2 about 260, 130, and 75 Torr, respectively, were in accordance with a venous admixture of about 1%. No substantial PCO2 differences between arterial blood and end-tidal gas (PaCO2 - PE'CO2) were found. The mean PaCO2 - PE'CO2 of 266 measurements in 70 rebreathing periods was -0.4 +/- 1.4 (SD) Torr. There was no correlation between PaCO2 - PE'CO2 and the level of arterial PCO2 or PO2. The mean PaCO2 - PE'CO2 became +0.1 Torr when the blood transit time from lungs to carotid artery (estimated at 6 s) and the rate of rise of bag PCO2 (4.5 Torr/min) were taken into account. These experimental results do not confirm the presence of significant PCO2 differences between arterial blood and alveolar gas in rebreathing equilibrium.