Arterial blood gas control in the upright versus recumbent Asian elephant

In the elephant, there is concern that lateral recumbency (LR) impairs respiratory muscle and lung function resulting in clinically significant arterial hypoxemia. Using healthy adult female Asian elephants (Elephas maximus, n=6), the hypothesis was tested that, given the O(2) binding characteristics of elephant blood, substantial reductions in arterial O(2) pressure (Pa(O(2))) in LR could be tolerated without lowering arterial O(2) content appreciably. Fifteen minutes of LR decreased Pa(O(2)) from 103+/-2 (upright, U) to 77+/-4 mmHg (P<0.05) and hemoglobin O(2) saturation (U, 97.8+/-0.1, LR, 95.3+/-0.5%, P<0.05). However, due to a recumbency-induced hemoconcentration, arterial O(2) content was unchanged (U, 18.2+/-2.4, LR, 18.3+/-2.1 ml O(2) per 100 ml). In addition, there was a mild hyperventilation in LR that reduced arterial CO(2) pressure (P(CO(2))) from 39.4+/-0.3 to 37.1+/-1.0 mmHg (P<0.05). These data indicate that the Asian elephant can endure at least short periods of LR without lowering arterial O(2) content.     

Ventilatory control and acid-base regulation across the menstrual cycle in oral contraceptive users

We examined the effect of menstrual cycle (MC) phase on acid-base regulation and ventilatory control at rest in monophasic oral contraceptive (OC) users. Twelve healthy women (25+/-1 years; mean+/-S.E.) were tested during the inactive (IP; 5.1+/-0.2 days) and active (AP; 21.1+/-0.7 days) pill phase of the MC. Central and peripheral chemoreflex responsiveness was examined using a modified CO(2) rebreathing procedure. Minute ventilation (V E), breathing pattern and metabolic rate were measured during 10 min of quiet, resting breathing. Blood for the determination of arterial P(CO2) (Pa(CO2)) and hydrogen ion concentration ([H(+)]); plasma concentrations of the strong ion difference ([SID]) and total weak acid ([A(tot)]); serum concentrations of progesterone ([P(4)]) and 17beta-estradiol ([E(2)]) were also obtained. Although [E(2)] (p<0.05) and [A(tot)] (p=0.05) were increased in the IP versus AP, MC phase had no significant effect on resting V E, breathing pattern, metabolic rate, [H(+)], Pa(CO2), [SID], [P(4)] and central or peripheral chemoreflex characteristics. Overall, OC had no significant physiological effect on acid-base regulation or ventilatory control at rest in healthy women. This may reflect suppression of endogenous fluctuations in circulating [P(4)] typically observed across the MC in healthy, eumenorrheic non-OC users.     

Cerebral blood flow sensitivity to CO2 measured with steady-state and Read's rebreathing methods

The ventilatory response to carbon dioxide (CO2) measured by the steady-state method is lower than that measured by Read's rebreathing method. A change in end-tidal P CO2 (PET CO2) results in a lower increment change in brain tissue P CO2 (Pt CO2) in the steady-state than with rebreathing: since Pt(CO2) determines the ventilatory response to CO2, the response is lower in the steady-state. If cerebral blood flow (CBF) responds to Pt CO2, the CBF-CO2 response should be lower in the steady-state than with rebreathing. Six subjects undertook two protocols, (a) steady-state: PET CO2 was held at 1.5 mmHg above normal (isocapnia) for 10 min, then raised to three levels of hypercapnia, (8 min each; 6.5, 11.5 and 16.5 mmHg above normal, separated by 4 min isocapnia). End-tidal P O2 was held at 300 mmHg; (b) rebreathing: subjects rebreathed via a 6 L bag filled with 6.5% CO2 in O2. Transcranial Doppler-derived CBF yielded a higher CBF-CO2 sensitivity in the steady-state than with rebreathing, suggesting that CBF does not respond to Pt CO2.     

Acid-base equilibrium during acute long-lasting experiments in artificially ventilated cats.

Experiments were carried out to study blood acid-base equilibrium in the cat during experiments with artificial ventilation. Blood acid-base equilibrium was examined in the arterial and venous blood by analyzing pH, carbon dioxide and oxygen partial pressure, and plasma bicarbonates. Artificial ventilation was regulated on the basis of this analysis; CO2 concentration in expired air was monitored throughout the experiment. An attempt was made to verify if artificial ventilation could be regulated indirectly only on the basis of CO2 concentration in expired air. The most appropriate acid-base equilibrium was maintained when CO2 concentration in expired air was kept within the range of 3.9-4.1%.     

Interactions of acid-base balance and hematocrit regulation during environmental respiratory gas challenges in developing chicken embryos (Gallus gallus)

How the determinants of hematocrit (Hct) - alterations in mean corpuscular volume (MCV) and/or red blood cell concentration ([RBC]) - are influenced by acid-base balance adjustments across development in the chicken embryo is poorly understood. We hypothesized, based on oxygen transport needs of the embryos, that Hct will increase during 1 day of hypercapnic hypoxia (5%CO(2), 15%O(2)) or hypoxia alone (0%CO(2), 15%O(2)), but decrease in response to hyperoxia (0%CO(2), 40%O(2)). Further, age-related differences in acid-base disturbances and Hct regulation may arise, because the O(2) transport and hematological regulatory systems are still developing in embryonic chickens. Our studies showed that during 1 day of hypoxia (with or without hypercapnia) Hct increased through both increased MCV and [RBC] in day 15 (d15) embryo, but only through increased MCV in d17 embryo and therefore enhancement of O(2) transport was age-dependent. Hypercapnia alone caused a ≈ 14% decrease in Hct through decreased [RBC] and therefore did not compensate for decreased blood oxygen affinity resulting from the Bohr shift. The 11% (d15) and 14% (d17) decrease in Hct during hyperoxia in advanced embryos was because of an 8% and 9% decrease, respectively, in [RBC], coupled with an associated 3% and 5% decrease in MCV. Younger, d13 embryos were able to metabolically compensate for respiratory acidosis induced by hypercapnic hypoxia, and so were more tolerant of disturbances in acid-base status induced via alterations in environmental respiratory gas composition than their more advanced counterparts. This counter-intuitive increased tolerance likely results from the relatively low [Formula: see text] and immature physiological functions of younger embryos.     

Ventilation and acid-base balance during graded activity in lizards

Arterial PCO2, hydrogen ion ([H+]a), and lactate ([L]a) concentrations, rates of metabolic CO2 production (VCO2) and O2 consumption (VO2), and effective alveolar ventilation (Veff) were determined in the lizards Varanus exanthematicus and Iguana iguana at rest and during steady-state treadmill exercise at 35 degrees C. In Varanus, VCO2 increased ninefold and VO2 sixfold without detectable rise in [L]a at running speeds below 1.0 to 1.5 km x h-1. In this range, Veff increased 12-fold resulting in decreased levels of PaCO2 and [H+]a. At higher speeds [L]a rose. Increments of 5 mM [L]a were accompanied by hyperventilation, reducing PaCO2 and thus maintaining [H+]a near its resting level. When [L]a increased further, [H+]a increased. Sustainable running speeds (0.3-0.5 km x h-1 and below) were often associated with increased VO2, VCO2, and [L]a in Iguana. Sixfold increases in VCO2 and 9-mM increments in [L]a were accompanied by sufficient increase in Veff (9-fold) to maintain [H+]a at or below its control level. When [L]a increased further, [H+]a increased. These results indicate that both lizard species maintain blood acid-base homeostasis rather effectively via ventilatory adjustments at moderate exercise intensities.     

The frequency of nerve impulses in single carotid body chemoreceptor afferent fibres recorded in vivo with intact circulation

1. The responses of single afferent fibres of carotid body chemoreceptors to independent changes in arterial O(2) and CO(2) tensions and pH were studied in the cat in vivo.2. The response curve obtained relating chemoreceptor activity to changes in arterial P(O2) was similar to an hyperbola; the frequency of nerve impulses at first decreased rapidly as the P(a,O2) was raised and then more slowly. The arterial P(O2) at which the slow decrease was reached varied among the different fibres; the mean level was 190 mm Hg (S.D. +/- 40 mm Hg).3. Single chemoreceptor afferent fibres continued to discharge even when the arterial P(O2) was more than 600 mm Hg.4. The discharges of single chemoreceptor afferent fibres increased both with increasing P(a,CO2) at constant pH and P(a,O2), and with increasing arterial H(+) at constant P(a,CO2) and P(a,O2).5. It is concluded that single carotid body chemoreceptor afferent fibres of the cat can be activated in vivo by an increase in either arterial H(+) or arterial P(CO2) as well as by a decrease in arterial P(O2).     

Effects of changes in PO2 and PCO2 and pH on the total vascular resistance of perfused cat kidneys

1. The effects of change in arterial P(O2), P(CO2) and pH on the total vascular resistance (RVR) of the perfused cat kidney have been separately measured and expressed as +/- percentage deviations from control values.2. Control levels in arterial blood were pH 7.38, P(-) (O2) 160 mm Hg, in equilibrium with 5% CO(2).3. Increase in P(O2) alone, in excess of 220 mm Hg, raised RVR reversibly reading 108% control levels at a P(O2) 280 mm Hg (P = < 0.001).4. High levels of P(O2) favoured the onset of ;outflow block', which was characterized by irreversible increase in RVR accompanied by rise in plasma filtration fraction (F.F.) and in the extraction ratio for p-aminohippuric acid (PAH extraction).5. Reduction in P(O2) to 80 mm Hg decreased RVR by 4% (P = < 0.001).6. RVR was not significantly affected by pH changes within the range 7.25-7.45. Lowering arterial pH to 7.15 raised RVR by 4% (P = < 0.001) reversibly. Increase in arterial pH to 7.56 raised RVR by 6% (P = < 0.001) reversibly.7. Changes in arterial P(CO2) produced large inverse reversible changes in RVR. Halving P(CO2) raised RVR by 18%; doubling P(CO2) decreased RVR by 25%.8. Changes in RVR caused by alteration of arterial pH or P(CO2) were not accompanied by changes either in F.F. or in PAH extraction.     

Acid-base balance and CO2 excretion in fish: unanswered questions and emerging models

Carbon dioxide (CO(2)) excretion and acid-base regulation in fish are linked, as in other animals, though the reversible reactions of CO(2) and the acid-base equivalents H(+) and HCO(3)(-): CO(2)+H(2)O<-->H(+)+HCO(3)(-). These relationships offer two potential routes through which acid-base disturbances may be regulated. Respiratory compensation involves manipulation of ventilation so as to retain CO(2) or enhance CO(2) loss, with the concomitant readjustment of the CO(2) reaction equilibrium and the resultant changes in H(+) levels. In metabolic compensation, rates of direct H(+) and HCO(3)(-) exchange with the environment are manipulated to achieve the required regulation of pH; in this case, hydration of CO(2) yields the necessary H(+) and HCO(3)(-) for exchange. Because ventilation in fish is keyed primarily to the demands of extracting O(2) from a medium of low O(2) content, the capacity to utilize respiratory compensation of acid-base disturbances is limited and metabolic compensation across the gill is the primary mechanism for re-establishing pH balance. The contribution of branchial acid-base exchanges to pH compensation is widely recognized, but the molecular mechanisms underlying these exchanges remain unclear. The relatively recent application of molecular approaches to this question is generating data, sometimes conflicting, from which models of branchial acid-base exchange are gradually emerging. The critical importance of the gill in acid-base compensation in fish, however, has made it easy to overlook other potential contributors. Recently, attention has been focused on the role of the kidney and particularly the molecular mechanisms responsible for HCO(3)(-) reabsorption. It is becoming apparent that, at least in freshwater fish, the responses of the kidney are both flexible and essential to complement the role of the gill in metabolic compensation. Finally, while respiratory compensation in fish is usually discounted, the few studies that have thoroughly characterized ventilatory responses during acid-base disturbances in fish suggest that breathing may, in fact, be adjusted in response to pH imbalances. How this is accomplished and the role it plays in re-establishing acid-base balance are questions that remain to be answered.     

暴发性肝功能衰竭大鼠肺血管壁通透性、血气的变化及其与内毒素血症的关系

本实验对硫代乙酰胺所致暴发性肝损伤大鼠肺血管壁通透性及血气的变化进行了观察。结果表明,肝损伤大鼠出现暴发性肝功能衰竭症状时,其肺血管对伊文思蓝的通透性增加(P<0.05),血浆内毒素水平亦较正常动物为高(P<0.05)。血气分析表现为动脉血CO_2分压增高(P<0.05);pH降低,且其水平与血浆内毒素浓度呈负相关(r=-0.730,P<0.05),70%大鼠出现混合性酸中毒,但动脉血氧分压及血氧饱和度无变化。     

Respiratory function during thermal tachypnoea in sheep

1. Four Merino wethers were exposed to dry bulb temperatures ranging from approximately 20 to 60 degrees C, and the concurrent changes in respiratory frequency, tidal volume, respiratory minute volume, alveolar ventilation, dead space ventilation, carbon dioxide output, rectal temperature, and arterial and mixed venous blood, CO(2) content, CO(2) partial pressure and pH were established.2. The respiratory response to heat exposure showed two phases. Respiratory minute volume was initially increased by a rise in the respiratory frequency, while tidal volume decreased. After more prolonged exposure there was a second phase in which respiratory minute volume was further increased by an increase in the tidal volume; respiratory frequency was now slower than in the first phase but was still well above control values.3. The increase in respiratory minute volume during the first phase of the response was restricted almost entirely to the respiratory dead space; changes in blood CO(2) and pH were slight. In the second phase, respiratory minute volume showed a much greater increase, and a change of alveolar ventilation to about 5 times the control level resulted in severe respiratory alkalosis.4. Contrary to findings in cattle, the slower, deeper form of respiration could be elicited even with rectal temperature in the normal range. This change in respiration appears to be the result of either peripheral thermoreceptor function or mechanical demands of the respiratory system. The neglect of control of acid-base balance during the second phase indicates the existence of a dominant thermal stimulus or modification of respiratory control mechanisms.     

Assessing acid-base status in circulatory failure. Differences between arterial and central venous blood

To assess arteriovenous differences in acid-base status, we measured the pH and partial pressure of carbon dioxide (PCO2) in blood drawn simultaneously from the arterial and central venous circulations in 26 patients with normal cardiac output, 36 patients with moderate and 5 patients with severe circulatory failure, and 38 patients with cardiac or cardiorespiratory arrest. The patients with normal cardiac output had the expected arteriovenous differences: venous pH was lower by 0.03 unit, and venous PCO2 was higher by 0.8 kPa (5.7 mm Hg). These differences widened only slightly in those with moderate cardiac failure. Additional simultaneous determinations in mixed venous blood from pulmonary arterial catheters were nearly identical to those in central venous blood. In the five hypotensive patients with severe circulatory failure there were substantial differences between the mean arterial and central venous pH (7.31 vs. 7.21) and PCO2 (5.8 vs. 9.0 kPa [44 vs. 68 mm Hg]). Large arteriovenous differences were present during cardiac arrest in patients whose ventilation was mechanically sustained, whether sodium bicarbonate had been administered (pH, 7.27 vs. 7.07; PCO2, 5.8 vs. 8.6 kPa [44 vs. 65 mm Hg]) or not (pH, 7.36 vs. 7.01; PCO2, 3.7 vs. 10.2 kPa [28 vs. 76 mm Hg]). By contrast, in patients with cardiorespiratory arrest, large arteriovenous differences were noted only when sodium bicarbonate had been given (pH, 7.24 vs. 7.01; PCO2, 9.5 vs. 16.9 kPa [71 vs. 127 mm Hg]). We conclude that both arterial and central venous blood samples are needed to assess acid-base status in patients with critical hemodynamic compromise. Although information about arterial blood gases is needed to assess pulmonary gas exchange, in the presence of severe hypoperfusion, the hypercapnia and acidemia at the level of the tissues are detected better in central venous blood.     

Difference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation

We investigated the acid-base condition of arterial and mixed venous blood during cardiopulmonary resuscitation in 16 critically ill patients who had arterial and pulmonary arterial catheters in place at the time of cardiac arrest. During cardiopulmonary resuscitation, the arterial blood pH averaged 7.41, whereas the average mixed venous blood pH was 7.15 (P less than 0.001). The mean arterial partial pressure of carbon dioxide (PCO2) was 32 mm Hg, whereas the mixed venous PCO2 was 74 mm Hg (P less than 0.001). In a subgroup of 13 patients in whom blood gases were measured before, as well as during, cardiac arrest, arterial pH, PCO2, and bicarbonate were not significantly changed during arrest. However, mixed venous blood demonstrated striking decreases in pH (P less than 0.001) and increases in PCO2 (P less than 0.004). We conclude that mixed venous blood most accurately reflects the acid-base state during cardiopulmonary resuscitation, especially the rapid increase in PCO2. Arterial blood does not reflect the marked reduction in mixed venous (and therefore tissue) pH, and thus arterial blood gases may fail as appropriate guides for acid-base management in this emergency.     

Carotid body thin slices: responses of glomus cells to hypoxia and K(+)-channel blockers

We describe the rat carotid body thin slice preparation, which allows to perform patch-clamp recording of membrane ionic currents and to monitor catecholamine secretion by amperometry in single glomus cells under direct visual control. We observed several electrophysiologically distinct cell classes within the same glomerulus. A voltage- and Ca(2+)-dependent component of the whole cell K(+) current was reversibly inhibited by low P(O(2)) (20 mmHg). Exposure of the cells to hypoxia elicited the appearance of spike-like exocytotic events. This response to hypoxia was reversible and required extracellular Ca(2+) influx. Addition of tetraethylammonium (TEA, 2-5 mM) to the extracellular solution induced in most (>95%) cells tested a secretory response similar to that elicited by low P(O(2)). Cells non-responsive to hypoxia but activated by exposure to high external K(+) were also stimulated by TEA. A secretory response similar to that of hypoxia or TEA was also observed after treatment of the cells with iberiotoxin to block selectively maxi-K(+) channels. Our data further support the view that membrane ion channels are critically involved in sensory transduction in the carotid body. We demonstrate that in intact glomus cells inhibition of voltage-dependent K(+) channels can contribute to initiate the secretory response to low P(O(2)).     

Serum potassium and acid-base parameters in severe dialysis-associated hyperglycemia treated with insulin therapy

We analyzed the changes in serum potassium concentration ([K]) and acid-base parameters in 43 episodes of dialysis-associated hyperglycemia (serum glucose level > 33.3 mmol/L), 22 of which were characterized as diabetic ketoacidosis (DKA) and the remaining 21 as nonketotic hyperglycemia (NKH). All episodes were treated with insulin therapy only. Age, gender, initial and final serum values of glucose, sodium, chloride, tonicity and osmolality did not differ between DKA and NKH. At presentation, serum values of [K] (DKA 6.2 +/- 1.3 mmol/L; NKH 5.2 +/- 1.5 mmol/L) and anion gap [AG] (DKA 27.2 +/- 6.4 mEq/L; NKH 15.4 +/- 3.5 mEq/L) were higher in DKA, whereas serum total carbon dioxide content [TCO2 ] (DKA 12.0 +/- 4.6 mmol/L; NKH 22.5 +/- 3.1 mmol/L), arterial blood pH (DKA 7.15 +/- 0.09; NKH 7.43 +/- 0.07) and arterial blood PaCO2 (DKA 26.2 +/- 12.3 mm Hg; NKH 34.5 +/- 6.7 mm Hg) were higher in NKH. At the end of insulin treatment, serum values of [K] (DKA 4.0 +/- 0.7 mmol/L, NKH 4.0 +/- 0.5 mmol/L), [AG] (DKA 16.3 +/- 5.4 mEq/L, NKH 14.9 +/- 3.0 mEq/L), [TCO2 ] (DKA 23.5 +/- 5.0 mmol/L, NKH 24.1 +/- 4.2 mmol/L), arterial blood pH (DKA 7.42 +/- 0.09, NKH 7.51 +/- 0.14) and arterial blood PaCO2 (DKA 31.8 +/- 6.7 mm Hg, NKH 34.2 +/- 8.3 mm Hg) did not differ between the two groups. Linear regression of the decrease in serum [K] value during treatment, (Delta[K]), on the presenting serum [K] concentration,([K]2 ), was: DKA, Delta[K] = 2.78 - 0.81 x [K]2 , r = -0.85, p < 0.001; NKH, Delta[K] = 2.44 - 0.71 x [K]2 , r = -0.90, p < 0.001. The slopes of the regressions were not significantly different. Stepwise logistic regression including both DKA and NKH cases identified the presenting serum [K] level and the change in serum [TCO2 ] value during treatment as the predictors of Delta[K] (R2 = 0.81). Hyperkalemia is a feature of severe hyperglycemia (DKA or NKH) occurring in patients on dialysis. Insulin administration brings about correction of DKA and return of serum [K] concentration to the normal range in the majority of the hyperglycemic episodes without the need for other measures. The initial serum [K] value and the change in serum [TCO2 ] level during treatment influence the decrease in serum [K] value during treatment of dialysis-associated hyperglycemia with insulin.     

Separation of carotid body chemoreceptor responses to O2 and CO2 by oligomycin and by antimycin A

The cat carotid chemoreceptor O2 and CO2 responses can be separated by oligomycin and by antimycin A. Both of these agents greatly diminish or abolish the chemoreceptor O2 response but not the nicotine or CO2 responses. After either oligomycin or antimycin, the responses to increases and decreases in arterial CO2 partial pressure (PaCO2) consisted of increases and decreases in activity characterized respectively by exaggerated overshoots and undershoots. These were eliminated by the carbonic anhydrase inhibitor, acetazolamide, suggesting that they resulted from changes in carotid body tissue pH. The steady-state PaCO2 response remaining after oligomycin was no longer dependent on arterial O2 partial pressure (PaO2). All effects of antimycin were readily reversible in about 20 min. The separation of the responses to O2 and CO2 indicates that there may be at least partially separate pathways of chemoreception for these two stimuli. The similarity of the oligomycin and antimycin results supports the metabolic hypothesis of chemoreception.     

The role of arterial oxygen tension in the respiratory response to localized heating of the hypothalamus and to hyperthermia

1. Rectal temperatures, respiratory rates, arterial blood gas tensions, arterial pH and the percentage of red cells in arterial blood have been measured in the unanaesthetized ox in a cool environment (15/12 degrees C, dry bulb/wet bulb [DB/WB]), in a hot, dry environment (40/21 degrees C, DB/WB), during hyperthermia, during infra-red irradiation, and during localized heating of the anterior hypothalamus. In some experiments the gas tensions and pH of mixed venous blood, and the percentage saturation of the arterial blood with oxygen, were also measured.2. In the cool environment at a mean rectal temperature (T(r)) of 38.8 degrees C and a respiratory rate (f) of 28/min the mean values obtained from six animals were: arterial oxygen tension (P(a, O) (2)), 93 mm Hg; arterial carbon dioxide tension (P(a, CO) (2)) 42 mm Hg; arterial pH 7.49; arterial oxygen saturation (S(a, O) (2)) 94%; arterial oxygen capacity (Cap(a, O) (2)) 13.6 vol.%; arterial packed cell volume (P.C.V.) 29%.3. Exposure to the hot, dry environment resulted in a small increase in the rectal temperature and thermal polypnoea, but there were no statistically significant changes in the blood gas tensions.4. During hyperthermia statistically significant increases occurred in rectal temperature, respiratory rate, P(a, O) (2), pH and arterial haematocrit, while the P(a, CO) (2) decreased. The venous oxygen tension (P(v, O) (2)) decreased also, and the tentative conclusion was made that although the oxygenation of arterial blood remained unimpaired during hyperthermia, tissue hypoxia may supervene. At very high levels of deep body temperature, some evidence for a secondary decrease in P(a, O) (2) was obtained.5. Localized heating of the anterior hypothalamus caused an increase in respiratory rate and in P(a, O) (2). The P(v, O) (2) increased also. These changes were considered to be due to increased cardiac output and diversion of blood to the skin.6. During infra-red irradiation of three animals at an environmental temperature of 40/21 degrees C, the respiratory rate increased, but the P(a, O) (2) decreased.     

Physiological mechanisms of hyperventilation during human pregnancy

This study examined the role of pregnancy-induced changes in wakefulness (or non-chemoreflex) and central chemoreflex drives to breathe, acid-base balance and female sex hormones in the hyperventilation of human pregnancy. Thirty-five healthy women were studied in the third trimester (TM(3); 36.3+/-1.0 weeks gestation; mean+/-S.D.) and again 20.2+/-7.8 weeks post-partum (PP). An iso-oxic hyperoxic rebreathing procedure was used to evaluate wakefulness and central chemoreflex drives to breathe. At rest, arterialized venous blood was obtained for the estimation of arterial PCO(2) (PaCO(2)) and [H(+)]. Blood for the determination of plasma strong ion difference ([SID]), albumin ([Alb]), as well as serum progesterone ([P(4)]) and 17beta-estradiol ([E(2)]) concentrations was also obtained at rest. Wakefulness and central chemoreflex drives to breathe, [P(4)] and [E(2)], ventilation and V CO(2) increased, whereas PaCO(2) and the central chemoreflex ventilatory recruitment threshold for PCO(2) (VRTCO(2)) decreased from PP to TM(3) (all p<0.01). The reductions in PaCO(2) were not related to the increases in [P(4)] and [E(2)]. The alkalinizing effects of reductions in PaCO(2) and [Alb] were partly offset by the acidifying effects of a reduced [SID], such that arterial [H(+)] was still reduced in TM(3) vs. PP (all p<0.001). A mathematical model of ventilatory control demonstrated that pregnancy-induced changes in wakefulness and central chemoreflex drives to breathe, acid-base balance, V CO(2) and cerebral blood flow account for the reductions in PaCO(2), [H(+)] and VRTCO(2). This is the first study to demonstrate that the hyperventilation and attendant hypocapnia/alkalosis of human pregnancy results from a complex interaction of pregnancy-induced changes in wakefulness and central chemoreflex drives to breathe, acid-base balance, metabolic rate and cerebral blood flow.