A control system for arterial blood gases

A system was developed to control arterial O2 and CO2 partial pressure (Pao2, and Paco2) simultaneously and independently of each other. The system makes changes in inspired fractional concentration of O2 and CO2 based on values for end-tidal O2 and CO2 partial pressure. The system was applied in 23 normal subjects. In attempts to maintain a Pao2 of 90 Torr and a Paco2 of 40 Torr, arterial blood gases were 91.1 +/- 6.5 (SD) Torr for Pao2 and 41.2 +/- 3.2 Torr for Paco2. In attempts to maintain a Pao2 of 40 Torr and a Paco2 of 40 Torr, arterial blood gases were 40.4 +/- 3.9 Torr for Pao2 and 38.9 +/- 2.5 Torr for Paco2. In attempts to maintain a Pao2 of 90 Torr and a Paco2 of 55 Torr, arterial blood gases were 98.1 +/- 11.5 Torr for Pao2 and 52.8 +/- 3.4 Torr for Paco2. Coefficients of variations ranged from 7.1 to 11.7% for Pao2 and 6.4 to 7.8% for Paco2.     

Arterial blood gases in conscious rats exposed to hypoxia, hypercapnia, or both.

Adult male rats were anesthetized and catheters were implanted in the caudal artery. Soon after recovery from short-lasting anesthesia, a total of 20 groups of six each were individually exposed to five different oxygen levels varying from 21.0 to 9.0% combined with four CO2 levels ranging from 0 to 12.9% at a mean barometric pressure of 744 Torr. Arterial blood samples were collected and analyzed for pH, Po2, and Pco2 before and near the end of 20-min exposures. During an air-breathing control period, pH averaged 7.466 plus or minus 0.020 SD, Paco2 41.2 plus or minus 1.9 Torr and Pao2 91.8 plus or minus 3.5 Torr. During hypoxia, Pao2 levels were similar to that of acutely hypoxic humans. Rats apparently differ from man in that blood buffering is greater, resulting in a higher pH during air breathing and a smaller [H-+] increase with increasing Paco2. Differences between arterial and inspired CO2 were about 10 Torr at 60 and 90 Torr Plco2 and were not influenced by Plo2.     

Cerebrovascular responsiveness to steady-state changes in end-tidal CO2 during passive heat stress.

This study tested the hypothesis that passive heat stress alters cerebrovascular responsiveness to steady-state changes in end-tidal CO(2) (Pet(CO(2))). Nine healthy subjects (4 men and 5 women), each dressed in a water-perfused suit, underwent normoxic hypocapnic hyperventilation (decrease Pet(CO(2)) approximately 20 Torr) and normoxic hypercapnic (increase in Pet(CO(2)) approximately 9 Torr) challenges under normothermic and passive heat stress conditions. The slope of the relationship between calculated cerebrovascular conductance (CBVC; middle cerebral artery blood velocity/mean arterial blood pressure) and Pet(CO(2)) was used to evaluate cerebrovascular CO(2) responsiveness. Passive heat stress increased core temperature (1.1 +/- 0.2 degrees C, P < 0.001) and reduced middle cerebral artery blood velocity by 8 +/- 8 cm/s (P = 0.01), reduced CBVC by 0.09 +/- 0.09 CBVC units (P = 0.02), and decreased Pet(CO(2)) by 3 +/- 4 Torr (P = 0.07), while mean arterial blood pressure was well maintained (P = 0.36). The slope of the CBVC-Pet(CO(2)) relationship to the hypocapnic challenge was not different between normothermia and heat stress conditions (0.009 +/- 0.006 vs. 0.009 +/- 0.004 CBVC units/Torr, P = 0.63). Similarly, in response to the hypercapnic challenge, the slope of the CBVC-Pet(CO(2)) relationship was not different between normothermia and heat stress conditions (0.028 +/- 0.020 vs. 0.023 +/- 0.008 CBVC units/Torr, P = 0.31). These results indicate that cerebrovascular CO(2) responsiveness, to the prescribed steady-state changes in Pet(CO(2)), is unchanged during passive heat stress.     

Hemodynamic effects of periodic obstructive apneas in sedated pigs with congestive heart failure.

Because of similar physiological changes such as increased left ventricular (LV) afterload and sympathetic tone, an exaggerated depression in cardiac output (CO) could be expected in patients with coexisting obstructive sleep apnea and congestive heart failure (CHF). To determine cardiovascular effects and mechanisms of periodic obstructive apnea in the presence of CHF, 11 sedated and chronically instrumented pigs with CHF (rapid pacing) were tested with upper airway occlusion under room air breathing (RA), O(2) breathing (O2), and room air breathing after hexamethonium (Hex). All conditions led to large negative swings in intrathoracic pressure (-30 to -39 Torr) and hypercapnia (PCO(2) approximately 60 Torr), and RA and Hex also caused hypoxia (to approximately 42 Torr). Relative to baseline, RA increased mean arterial pressure (from 97.5 +/- 5.0 to 107.3 +/- 5.7 Torr, P < 0.01), systemic vascular resistance, LV end-diastolic pressure, and LV end-systolic length while it decreased CO (from 2.17 +/- 0.27 to 1.52 +/- 0.31 l/min, P < 0.01), stroke volume (SV; from 23.5 +/- 2.4 to 16.0 +/- 4.0 ml, P < 0.01), and LV end-diastolic length (LVEDL). O2 and Hex decreased mean arterial pressure [from 102.3 +/- 4.1 to 16.0 +/- 4.0 Torr (P < 0.01) with O2 and from 86.0 +/- 8.5 to 78.1 +/- 8.7 Torr (P < 0.05) with Hex] and blunted the reduction in CO [from 2.09 +/- 0.15 to 1.78 +/- 0.18 l/ml for O2 and from 2.91 +/- 0.43 to 2.50 +/- 0.35 l/ml for Hex (both P < 0.05)] and SV. However, the reduction in LVEDL and LV end-diastolic pressure was the same as with RA. There was no change in systemic vascular resistance and LVEDL during O2 and Hex relative to baseline. In the CHF pigs during apnea, there was an exaggerated reduction in CO and SV relative to our previously published data from normal sedated pigs under similar conditions. The primary difference between CHF (present study) and the normal animals is that, in addition to increased LV afterload, there was a decrease in LV preload in CHF contributing to SV depression not seen in normal animals. The decrease in LV preload during apneas in CHF may be related to effects of ventricular interdependence.     

Effect of upper airway carbon dioxide on ventilation and blood gases in the awake pony

Carbon dioxide concentrations were increased during expiration in the upper one-half of the trachea, pharynx, and nasal sinuses to determine if elevation of upper airway CO2 would alter breathing or arterial blood gases in the awake pony. Carbon dioxide (100%) was injected into the midcervical trachea via a chronically implanted transcutaneous cannula during the first part of the animal's expiration. This maneuver elevated upper airway expiratory CO2 concentrations but prevented any exogenous CO2 from entering the lung and being absorbed into the arterial blood. Twelve experiments were performed on six ponies in which upper airway CO2 was elevated 2, 4, and 6% above the normal expired CO2 concentrations. Tidal volume increased in a dose dependent manner during upper airway CO2 exposure, but total ventilation was unchanged from base-line measurements made while the animal breathed room air. Arterial Po2 also increased during upper airway CO2 administration, reaching a mean value 6 Torr (1 Torr = 133.322 Pa) greater than the base-line values at the +6% CO2 exposure. We conclude that upper airway CO2 exposure alters breathing pattern slightly (increases tidal volume) and increases arterial PO2 in the awake pony.     

Validation of a maskless CO2-response test for sleep and infant studies

The Hazinski method is an indirect, noninvasive, and maskless CO2-response test useful in infants or during sleep. It measures the classic CO2-response slope (i.e., delta VI/delta PCO2) divided by resting ventilation Sr = (VI'--VI')/(VI'.delta PCO2) between low (')- and high (')-inspired CO2 as the fractional increase of alveolar ventilation per Torr rise of PCO2. In steady states when CO2 excretion (VCO2') = VCO2', Hazinski CO2-response slope (Sr) may be computed from the alveolar exchange equation as Sr = (PACO2'--PICO2')/(PACO2'--PICO2') where PICO2 is inspired PCO2. To avoid use of a mask or mouthpiece, the subject breathes from a hood in which CO2 is mixed with inspired air and a transcutaneous CO2 electrode is used to estimate alveolar PCO2 (PACO2). To test the validity of this method, we compared the slopes measured simultaneously by the Hazinski and standard steady-state methods using a pneumotachograph, mask, and end-tidal, arterial, and four transcutaneous PCO2 samples in 15-min steady-state challenges at PICO2 23.5 +/- 4.5 and 37 +/- 4.1 Torr. Sr was computed using PACO2 and arterial PCO2 (PaCO2) as well as with the four skin PCO2 (PSCO2) values. After correction for apparatus dead space, the standard method was normalized to resting VI = 1, and its CO2 slope was designated directly measured normalized CO2 slope (Sx), permitting error to be calculated as Sr/Sx.(ABSTRACT TRUNCATED AT 250 WORDS)     

Control of exercise hyperpnea during hypercapnia in humans

Previous studies have yielded conflicting results on the ventilatory response to CO2 during muscular exercise. To obviate possible experimental errors contributing to such variability, we have examined the CO2-exercise interaction in terms of the ventilatory response to exercise under conditions of controlled hypercapnia. Eight healthy male volunteers underwent a sequence of 5-min incremental treadmill exercise runs from rest up to a maximum CO2 output (VCO2) of approximately 1.5 l . min-1 in four successive steps. The arterial PCO2 (PaCO2) at rest was stabilized at the control level or up to 14 Torr above control by adding 0-6% CO2 to the inspired air. Arterial isocapnia (SD = 1.2 Torr) throughout each exercise run was maintained by continual adjustment of the inspired PCO2. At all PaCO2 levels the response in total ventilation (VE) was linearly related to exercise VCO2. Hypercapnia resulted in corresponding increases in both the slope (S) and zero intercept (V0) of the VE-VCO2 curve; these being directly proportional to the rise in PaCO2 (means +/- SE: delta S/ delta PaCO2, 2.73 +/- 0.28 Torr-1; delta V0/ delta PaCO2, 1.67 +/- 0.18 l . min-1 . Torr-1). Thus the ventilatory response to concomitant hypercapnia and exercise was characterized by a synergistic (additive plus multiplicative) effect, suggesting a positive interaction between these stimuli. The increased exercise sensitivity in hypercapnia is qualitatively consistent with the hypothesis that VE is controlled to minimize the conflicting challenges due to chemical drive and the mechanical work of breathing (Poon, C. S. In: Modelling and Control of Breathing, New York: Elsevier, 1983, p. 189-196).     

Fetal breathing and sleep state responses to graded carboxyhemoglobinemia in sheep

To investigate CO effects on brain oxygenation, graded carboxyhemoglobinemia (HbCO) was produced in nine unanesthetized fetal sheep by infusing CO-laden erythrocytes in exchange for fetal blood. For the 1st h after this procedure, the mean fetal carboxyhemoglobin levels were 16.5 +/- 0.4% [control (C) = 1.4 +/- 0.4%] for mild HbCO, 22.7 +/- 0.6% (C = 1.8 +/- 0.4%) for moderate HbCO, and 27.8 +/- 0.5% (C = 2.1 +/- 0.7%) for severe HbCO. This induction of HbCO significantly reduced mean preductal arterial PO2 values to 4.3 Torr below control for mild HbCO, 4.6 Torr below control for moderate HbCO, and 5.5 Torr below control for severe HbCO. The respective arterial O2 contents were decreased by 17, 21, and 29%. Mean arterial pH was lowered only during severe HbCO, and arterial PCO2 values were unchanged. HbCO produced a fetal tachycardia. Mean arterial blood pressure was only increased during severe HbCO. The incidences of rapid eye movements and breathing activity were decreased by HbCO in a dose-dependent manner. When related to calculated brain tissue PO2, these decreases were similar to those measured during hypoxic hypoxia and anemia, suggesting that carboxyhemoglobin effects result solely from diminished oxygenation. It is concluded that 1) the peripheral arterial chemoreceptors in the fetus apparently have little effect on hypoxic inhibition of breathing and 2) the carboxyhemoglobin concentrations required to inhibit fetal breathing are greater than those likely to be encountered clinically.     

In vivo regulation of plasma [H+] in ponies during acute changes in PCO2

The major objective of this study was to test the hypothesis that in ponies the change in plasma [H+] resulting from a change in PCO2 (delta H+/delta PCO2) is less under acute in vivo conditions than under in vitro conditions. Elevation of inspired CO2 and lowering of inspired O2 (causing hyperventilation) were used to respectively increase and decrease arterial PCO2 (Paco2) by 5-8 Torr from normal. Arterial and mixed venous blood were simultaneously sampled in 12 ponies during eucapnia and 5-60 min after Paco2 had changed. In vitro data were obtained by equilibrating blood in a tonometer at five different levels of PCO2. The in vitro slopes of the H+ vs. PCO2 relationships were 0.73 +/- 0.01 and 0.69 +/- 0.01 neq.1-1.Torr-1 for oxygenated and partially deoxygenated blood, respectively. These slopes were greater (P less than 0.001) than the in vivo H+ vs. PCO2 slopes of 0.61 +/- 0.03 and 0.57 +/- 0.03 for arterial and mixed venous blood, respectively. The delta HCO3-/delta pH (Slykes) was 15.4 +/- 1.1 and 17.0 +/- 1.1 for in vitro oxygenated and partially deoxygenated blood, respectively. These values were lower (P less than 0.001) than the in vivo values of 23.3 +/- 2.7 and 25.2 +/- 4.7 Slykes for arterial and mixed venous blood, respectively. In vitro, plasma strong ion difference (SID) increased 4.5 +/- 0.2 meq/l (P less than 0.001) when Pco2 was increased from 25 to 55 Torr. A 3.5-meq/l decrease in [Cl-] (P less than 0.001) and a 1.3 +/- 0.1 meq/l increase in [Na+] (P less than 0.001) accounted for the SID change.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ventilatory control during exercise with peripheral chemoreceptor stimulation: hypoxia vs. domperidone

Hypoxia potentiates the ventilatory response to exercise, eliciting a greater decrease in arterial PCO2 (PaCO2) from rest to exercise than in normoxia. The mechanism of this hypoxia-exercise interaction requires intact carotid chemoreceptors. To determine whether carotid chemoreceptor stimulation alone is sufficient to elicit the mechanism without whole body hypoxia, ventilatory responses to treadmill exercise were compared in goats during hyperoxic control conditions, moderate hypoxia (PaO2 = 38-44 Torr), and peripheral chemoreceptor stimulation with the peripheral dopamine D2-receptor antagonist, domperidone (Dom; 0.5 mg/kg iv). Measurements with Dom were made in both hyperoxia (Dom) and hypoxia (Dom/hypoxia). Finally, ventilatory responses to inspired CO2 at rest were compared in each experimental condition because enhanced CO2 chemoreception might be expected to blunt the PaCO2 decrease during exercise. At rest, PaCO2 decreased from control with Dom (-5.0 +/- 0.9 Torr), hypoxia (-4.1 +/- 0.5 Torr), and Dom/hypoxia (-11.1 +/- 1.2 Torr). The PaCO2 decrease from rest to exercise was not significantly different between control (-1.7 +/- 0.6 Torr) and Dom (-1.4 +/- 0.8 Torr) but was significantly greater in hypoxia (-4.3 +/- 0.7 Torr) and Dom/hypoxia (-3.5 +/- 0.9 Torr). The slope of the ventilation vs. CO2 production relationship in exercise increased with Dom (16%), hypoxia (18%), and Dom/hypoxia (68%). Ventilatory responses to inspired CO2 at rest increased from control to Dom (236%) and Dom/hypoxia (295%) and increased in four of five goats in hypoxia (mean 317%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased propensity for apnea via dopamine-induced carotid body inhibition in sleeping dogs.

We determined the effects of specific carotid body chemoreceptor inhibition on the propensity for apnea during sleep. We reduced the responsiveness of the carotid body chemoreceptors using intravenous dopamine infusions during non-rapid eye movement sleep in six dogs. Then we quantified the difference in end-tidal Pco(2) (Pet(CO(2))) between eupnea and the apneic threshold, the "CO(2) reserve," by gradually reducing Pet(CO(2)) transiently with pressure support ventilation at progressively increased tidal volume until apnea occurred. Dopamine infusions decreased steady-state eupneic ventilation by 15 +/- 6%, causing a mean CO(2) retention of 3.9 +/- 1.9 mmHg and a brief period of ventilatory instability. The apneic threshold Pet(CO(2)) rose 5.1 +/- 1.9 Torr; thus the CO(2) reserve was narrowed from -3.9 +/- 0.62 Torr in control to -2.7 +/- 0.78 Torr with dopamine. This decrease in the CO(2) reserve with dopamine resulted solely from the 20.5 +/- 11.3% increase in plant gain; the slope of the ventilatory response to CO(2) below eupnea was unchanged from normal. We conclude that specific carotid chemoreceptor inhibition with dopamine increases the propensity for apnea during sleep by narrowing the CO(2) reserve below eupnea. This narrowing is due solely to an increase in plant gain as the slope of the ventilatory response to CO(2) below eupnea was unchanged from normal control. These findings have implications for the role of chemoreceptor inhibition/stimulation in the genesis of apnea and breathing periodicity during sleep.     

Systemic hemodynamics affecting cardiac output during hypocapnic and hypercapnic hypoxia

Systemic hemodynamic adjustments involved in the control of cardiac output (CO) were examined in chronically instrumented unanesthetized sheep inhaling gas mixtures resulting in hypocapnic hypoxia (H) [arterial pH (pHa) = 7.53, arterial partial pressure of O2 (Pao2) = 30 Torr, arterial partial pressure of CO2 (Paco2) = 29 Torr] or hypercapnic hypoxia (HCH) (pHa = 7.14, Pao2 = 34 Torr, Paco2 = 72 Torr) for 1 h. H (n = 7) and HCH (n = 6) resulted in 26% and 61% increases in CO, respectively, and mean systemic arterial pressure rose to a greater extent during HCH. Both H and HCH resulted in increased blood flow (microsphere method) to the peripheral systemic circulation including the brain, heart, diaphragm, and nonrespiratory skeletal muscle (the latter blood flow increased 120% during H and 380% during HCH). Gastrointestinal and renal blood flow remained unchanged during H and HCH. Transit time of green dye from the pulmonary artery to regional veins in the hindlimb and intestine was 5.0 and 8.2 s, respectively, during base-line conditions and remained unchanged with HCH. During HCH, regional O2 consumption increased 274% for the hindlimb and decreased 39% for the intestine. Total catecholamines rose 250% during H and 3,700% during HCH. During hypocapnic and hypercapnic hypoxia, CO is augmented in part by systemic hemodynamic adjustments that include a redistribution of blood flow and a translocation of blood volume to the fast transit time peripheral systemic circuit. The sympathetic nervous system may play an important role in mediating these systemic hemodynamic adjustments.     

Costal diaphragmatic O2 and lactate extraction in laryngeal hemiplegic ponies during exercise

Diaphragmatic O2 and lactate extraction were examined in seven healthy ponies during maximal exercise (ME) carried out without, as well as with, inspiratory resistive breathing. Arterial and diaphragmatic venous blood were sampled simultaneously at rest and at 30-s intervals during the 4 min of ME. Experiments were carried out before and after left laryngeal hemiplegia (LH) was produced. During ME, normal ponies exhibited hypocapnia, hemoconcentration, and a decrease in arterial PO2 (PaO2) with insignificant change in O2 saturation. In LH ponies, PaO2 and O2 saturation decreased well below that in normal ponies, but because of higher hemoglobin concentration, arterial O2 content exceeded that in normal ponies. Because of their high PaCO2 during ME, acidosis was more pronounced in LH animals despite similar lactate values. Diaphragmatic venous PO2 and O2 saturation decreased with ME to 15.5 +/- 0.9 Torr and 18 +/- 0.5%, respectively, at 120 s of exercise in normal ponies. In LH ponies, corresponding values were significantly less: 12.4 +/- 1.3 Torr and 15.5 +/- 0.7% at 120 s and 9.8 +/- 1.4 Torr and 14.3 +/- 0.6% at 240 s of ME. Mean phrenic O2 extraction plateaued at 81 and 83% in normal and LH animals, respectively. Significant differences in lactate concentration between arterial and phrenic-venous blood were not observed during ME. It is concluded that PO2 and O2 saturation in the phrenic-venous blood of normal ponies do not reach their lowest possible values even during ME. Also, the healthy equine diaphragm, even with the added stress of inspiratory resistive breathing, did not engage in net lactate production.     

Somatostatin inhibits the ventilatory response to hypoxia in humans

The effects of a 90-min infusion of somatostatin (1 mg/h) on ventilation and the ventilatory responses to hypoxia and hypercapnia were studied in six normal adult males. Minute ventilation (VE) was measured with inductance plethysmography, arterial 02 saturation (SaO2) was measured with ear oximetry, and arterial PCO2 (Paco2) was estimated with a transcutaneous CO2 electrode. The steady-state ventilatory response to hypoxia (delta VE/delta SaO2) was measured in subjects breathing 10.5% O2 in an open circuit while isocapnia was maintained by the addition of CO2. The hypercapnic response (delta VE/delta PaCO2) was measured in subjects breathing first 5% and then 7.5% CO2 (in 52-55% O2). Somatostatin greatly attenuated the hypoxic response (control mean -790 ml x min-1.%SaO2 -1, somatostatin mean -120 ml x min-1.%SaO2 -1; P less than 0.01), caused a small fall in resting ventilation (mean % fall - 11%), but did not affect the hypercapnic response. In three of the subjects progressive ventilatory responses (using rebreathing techniques, dry gas meter, and end-tidal Pco2 analysis) and overall metabolism were measured. Somatostatin caused similar changes (mean fall in hypoxic response -73%; no change in hypercapnic response) and did not alter overall O2 consumption nor CO2 production. These results show an hitherto-unsuspected inhibitory potential of this neuropeptide on the control of breathing; the sparing of the hypercapnic response is suggestive of an action on the carotid body but does not exclude a central effect.     

Ventilatory response of the sleeping newborn to CO2 during normoxic rebreathing

The ventilatory response of the newborn to CO2 was studied using a rebreathing method that minimized changes in arterial PO2 during the test. The aim was to study the variability of the ventilatory response to CO2 and take this into account to assess the relative magnitude of the response to CO2 during rapid-eye-movement (REM) sleep and quiet sleep (QS). Five full-term babies aged 4-6 days were given 5% CO2 in air to rebreathe for 1.5-3 min. O2 was added to the rebreathing circuit to maintain arterial O2 saturation and transcutaneous PO2 (Ptco2) at prerebreathing levels. Tests were repeated four to five times in REM sleep and QS. Mean Ptco2 levels varied between individuals but were similar during REM sleep and QS tests for each subject. The mean coefficient of variability of the ventilatory response was 35% (range 15-77%) during QS and 120% (range 32-220%) during REM sleep. PtcO2 fluctuations during tests [6.0 +/- 3.0 (SD) Torr, range 1-13 Torr] were not correlated with ventilatory response. Overall the ventilatory response was significantly lower in REM sleep than in QS (12.2 +/- 3.0 vs. 38.7 +/- 3.0 ml.min-1.Torr-1.kg-1, P less than 0.001; 2-way analysis of variance) due to a small (nonsignificant) fall in the tidal volume response and a significant fall in breathing rate. In 12 REM sleep tests there was no significant ventilatory response; mean inspiratory flow increased significantly during 8 of these 12 tests. We conclude that there is a significant decrease in the ventilatory response of the newborn to CO2 rebreathing during REM sleep compared with QS.     

Relationship of CSF pH, O2, and CO2 responses in metabolic acidosis and alkalosis in humans

The effect of induced metabolic acidosis (48 h of NH4Cl ingestion, BE - 10.6 +/- 1.1) and alkalosis (43 h of NaHCO3- ingestion BE 8.8 +/- 1.6) on arterial and lumber CSF pH, Pco2, and HCO3- and ventilatory responses to CO2 and to hypoxia was assessed in five healthy men. In acidosis lumbar CSF pH rose 0.033 +/- 0.02 (P less than 0.05). In alkalosis CSF pH was unchanged. Ventilatory response lines to CO2 at high O2 were displaced to the left in acidosis (9.0 +/- 1.4 Torr) and to the right in alkalosis (4.5 +/- 1.5 Torr) with no change in slope. The ventilatory response to hypoxia (delta V40) was increased in acidosis (P less than 0.05) and it was decreased in four subjects in alkalosis (P, not significant). We conclude that the altered ventilatory drives of steady-state metabolic imbalance are mediated by peripheral chemoreceptors, and in acidosis the medullary respiratory chemoreceptor drive is decreased.     

Measurement of the CO2 apneic threshold in newborn infants: possible relevance for periodic breathing and apnea.

We measured the PCO2 apneic threshold in preterm and term infants. We hypothesized that, compared with adult subjects, the PCO2 apneic threshold in neonates is very close to the eupneic PCO2, likely facilitating the appearance of periodic breathing and apnea. In contrast with adults, who need to be artificially hyperventilated to switch from regular to periodic breathing, neonates do this spontaneously. We therefore measured the apneic threshold as the average alveolar PCO2 (PaCO2) of the last three breaths of regular breathing preceding the first apnea of an epoch of periodic breathing. We also measured the PaCO2 of the first three breaths of regular breathing after the last apnea of the same periodic breathing epoch. In preterm infants, eupneic PaCO2 was 38.6 +/- 1.4 Torr, the preperiodic PaCO2 apneic threshold was 37.3 +/- 1.4 Torr, and the postperiodic PaCO2 was 37.2 +/- 1.4 Torr. In term infants, the eupneic PaCO2 was 39.7 +/- 1.1 Torr, the preperiodic PaCO2 apneic threshold was 38.7 +/- 1.0 Torr, and the postperiodic value was 37.9 +/- 1.2 Torr. This means that the PaCO2 apneic thresholds were 1.3 +/- 0.1 and 1.0 +/- 0.2 Torr below eupneic PaCO2 in preterm and term infants, respectively. The transition from eupneic PaCO2 to PaCO2 apneic threshold preceding periodic breathing was accompanied by a minor and nonsignificant increase in ventilation, primarily related to a slight increase in frequency. The findings suggest that neonates breathe very close to their PCO2 apneic threshold, the overall average eupneic PCO2 being only 1.15 +/- 0.2 Torr (0.95-1.79, 95% confidence interval) above the apneic threshold. This value is much lower than that reported for adult subjects (3.5 +/- 0.4 Torr). We speculate that this closeness of eupneic and apneic PCO2 thresholds confers great vulnerability to the respiratory control system in neonates, because minor oscillations in breathing may bring eupneic PCO2 below threshold, causing apnea.     

Hypoxic pulmonary vasoconstriction during steady and pulsatile flow in ferrets

We examined the effects of hypoxia and pulsatile flow on the pressure-flow relationships in the isolated perfused lungs of Fitch ferrets. When perfused by autologous blood from a pump providing a steady flow of 60 ml/min, the mean pulmonary arterial pressure rose from 14.6 to 31.3 Torr when alveolar PO2 was reduced from 122 to 46 Torr. This hypoxic pressor response was characterized by a 10.1-Torr increase in the pressure-axis intercept of the extrapolated pressure-flow curves and an increase in the slope of these curves from 130 to 240 Torr X l-1 X min. With pulsatile perfusion from a piston-type pump, mean pulmonary arterial pressure increased from 17.5 to 36.3 Torr at the same mean flow. This hypoxic pressor response was also characterized by increases in the intercept pressure and slope of the pressure-flow curves. When airway pressure was raised during hypoxia, the intercept pressure increased further to 25 +/- 1 Torr with a further increase in vascular resistance to 360 Torr X l-1 X min. Thus, in contrast to the dog lung, in the ferret lung pulsatile perfusion does not result in lower perfusion pressures during hypoxia when compared with similar mean levels of steady flow. Since the effects of high airway pressure and hypoxia are additive, they appear to act at or near the same site in elevating perfusion pressure.     

Evidence for tissue diffusion limitation of VO2max in normal humans

We recently found [at approximately 90% maximal O2 consumption (VO2max)] that as inspiratory PO2 (PIO2) was reduced, VO2 and mixed venous PO2 (PVO2) fell together along a straight line through the origin, suggesting tissue diffusion limitation of VO2max. To extend these observations to VO2max and directly examine effluent venous blood from muscle, six normal men cycled at VO2max while breathing air, 15% O2 and 12% O2 in random order on a single day. From femoral venous, mixed venous, and radial arterial samples, we measured PO2, PCO2, pH, and lactate and computed mean muscle capillary PO2 by Bohr integration between arterial (PaO2) and femoral venous PO2 (PfvO2). VO2 and CO2 production (VCO2) were measured by expired gas analysis, VO2max averaged 61.5 +/- 6.2 (air), 48.6 +/- 4.8 (15% O2), and 38.1 +/- 4.1 (12% O2) ml.kg-1.min-1. Corresponding values were 16.8 +/- 5.6, 14.4 +/- 5.0, and 12.0 +/- 5.0 Torr for PfVO2; 23.6 +/- 3.2, 19.1 +/- 4.2, and 16.2 +/- 3.5 Torr for PVO2; and 38.5 +/- 5.4, 30.3 +/- 4.1, and 24.5 +/- 3.6 Torr for muscle capillary PO2 (PmCO2). Each of the PO2 variables was linearly related to VO2max (r = 0.99 each), with an intercept not different from the origin. Similar results were obtained when the subjects were pushed to a work load 30 W higher to ensure that VO2max had been achieved. By extending our prior observations 1) to maximum VO2 and 2) by direct sampling of femoral venous blood, we conclude that tissue diffusion limitation of VO2max may be present in normal humans. In addition, since PVO2, PfVO2, and PmCO2 all linearly relate to VO2max, we suggest that whichever of these is most readily obtained is acceptable for further evaluation of the hypothesis.     

Chronic intermittent hypoxia increases the CO2 reserve in sleeping dogs.

We hypothesized that chronic intermittent hypoxia (CIH) would induce a predisposition to apnea in response to induced hypocapnia. To test this, we used pressure support ventilation to quantify the difference in end-tidal partial pressure of CO(2) (Pet(CO(2))) between eupnea and the apneic threshold ("CO(2) reserve") as an index of the propensity for apnea and unstable breathing during sleep, both before and following up to 3-wk exposure to chronic intermittent hypoxia in dogs. CIH consisted of 25 s of Pet(O(2)) = 35-40 Torr followed by 35 s of normoxia, and this pattern was repeated 60 times/h, 7-8 h/day for 3 wk. The CO(2) reserve was determined during non-rapid eye movement sleep in normoxia 14-16 h after the most recent hypoxic exposure. Contrary to our hypothesis, the slope of the ventilatory response to CO(2) below eupnea progressively decreased during CIH (control, 1.36 +/- 0.18; week 2, 0.94 +/- 0.12; week 3, 0.73 +/- 0.05 l.min(-1).Torr(-1), P < 0.05). This resulted in a significant increase in the CO(2) reserve relative to control (P < 0.05) following both 2 and 3 wk of CIH (control, 2.6 +/- 0.6; week 2, 3.7 +/- 0.8; week 3, 4.5 +/- 0.9 Torr). CIH also 1) caused no change in eupneic, air breathing Pa(CO(2)); 2) increased the slope of the ventilatory response to hypercapnia after 2 wk but not after 3 wk compared with control; and 3) had no effect on the ventilatory response to hypoxia. We conclude that 3-wk CIH reduced the sensitivity of the ventilatory response to transient hypocapnia and thereby increased the CO(2) reserve, i.e., the propensity for apnea was reduced.