Hypoxemia In Lambs Research Articles

The Action of 2-Aminoethyldiphenyl Borinate on the Pulmonary Arterial Hypertension and Remodeling of High-Altitude Hypoxemic Lambs.

Calcium signaling is key for the contraction, differentiation, and proliferation of pulmonary arterial smooth muscle cells. Furthermore, calcium influx through store-operated channels (SOCs) is particularly important in the vasoconstrictor response to hypoxia. Previously, we found a decrease in pulmonary hypertension and remodeling in normoxic newborn lambs partially gestated under chronic hypoxia, when treated with 2-aminoethyldiphenyl borinate (2-APB), a non-specific SOC blocker. However, the effects of 2-APB are unknown in neonates completely gestated, born, and raised under environmental hypoxia. Accordingly, we studied the effects of 2-APB-treatment on the cardiopulmonary variables in lambs under chronic hypobaric hypoxia. Experiments were done in nine newborn lambs gestated, born, and raised in high altitude (3,600 m): five animals were treated with 2-APB [intravenous (i.v.) 10 mg kg–1] for 10 days, while other four animals received vehicle. During the treatment, cardiopulmonary variables were measured daily, and these were also evaluated during an acute episode of superimposed hypoxia, 1 day after the end of the treatment. Furthermore, pulmonary vascular remodeling was assessed by histological analysis 2 days after the end of the treatment. Basal cardiac output and mean systemic arterial pressure (SAP) and resistance from 2-APB- and vehicle-treated lambs did not differ along with the treatment. Mean pulmonary arterial pressure (mPAP) decreased after the first day of 2-APB treatment and remained lower than the vehicle-treated group until the third day, and during the fifth, sixth, and ninth day of treatment. The net mPAP increase in response to acute hypoxia did not change, but the pressure area under the curve (AUC) during hypoxia was slightly lower in 2-APB-treated lambs than in vehicle-treated lambs. Moreover, the 2-APB treatment decreased the pulmonary arterial wall thickness and the α-actin immunoreactivity and increased the luminal area with no changes in the vascular density. Our findings show that 2-APB treatment partially reduced the contractile hypoxic response and reverted the pulmonary vascular remodeling, but this is not enough to normalize the pulmonary hemodynamics in chronically hypoxic newborn lambs.

Brain Cell Function during Hypoxemia in Near-Term Lambs: A Near-Infrared Spectroscopy Study

Background: Sufficient O₂ supply to the brain is necessary for adequate cerebral energy metabolism, function and growth. Objectives: To elucidate the relation between changes in cerebral arterial O₂ content and cerebral O₂ supply and changes in the oxygenation state of cerebral hemoglobin, and to determine whether concentration changes in oxyhemoglobin (ΔcO₂Hb), deoxyhemoglobin (ΔcHHb), and cerebral arterial oxygenation (ΔcHbD; the difference between ΔcO₂Hb and ΔcHHb), and cerebral blood volume (ΔCBV) can be used to assess the decline in brain cell function during hypoxemia in lambs born near term. Methods: 17 preterm lambs were delivered at a mean gestational age of 133 days. Decreases in cerebral arterial oxygen content were induced by a stepwise reduction in inspired oxygen concentration. Mean values of all continuous variables were calculated over the last 180 s of each hypoxemic level. Cerebral arterial blood gases were analyzed at the end of each level to calculate cerebral arterial O₂ content and cerebral O₂ supply. Results: Changes in cerebral arterial O₂ content and cerebral O₂ supply were positively linearly related with ΔcO₂Hb and ΔcHbD, and negatively with ΔcHHb and the concentration changes in total hemoglobin. Electrocortical brain activity remained stable until the cO₂Hb and cHbD decreased to >3.0 ± 0.9 and >8.1 ± 1.9 (mean ± SD) µmol/100 g, respectively, and cHHb and CBV increased to >4.3 ± 1.7 and 1.37 ± 0.48 ml/100 g, respectively, as compared to baseline. Conclusions: Changes in cerebral arterial O₂ content and cerebral O₂ supply are adequately reflected by changes in the oxygenation state of cerebral hemoglobin. Concentration changes in ΔcO₂Hb, ΔcHHb, ΔcHbD and ΔCBV can be used to assess the decline in brain cell function during hypoxemia in lambs born near term.

Level of ventilation influences the cardiovascular response to hypoxemia in lambs

Newborn animals of a number of species display a brisk increase in ventilation followed by a gradual drop toward or below baseline within minutes of exposure to acute hypoxemia. Heart rate and cardiac output (a determinant of systemic oxygen transport along with the arterial oxygen content) appear to follow a similar pattern, but whether or not the cardiovascular response is influenced by the respiratory response is unknown. We therefore carried out experiments in which the level of ventilation was controlled during normoxemia and hypoxemia to test the hypothesis that the level of ventilation influences the cardiovascular response to acute hypoxemia. Six lambs ranging in age from 17 to 22 days were anesthetized, tracheostomized, and instrumented for measurement of cardiovascular variables. A recovery period of at least 3 days was allowed before the study when each lamb was artificially ventilated with a mixture of 70% nitrous oxide and 30% oxygen in nitrogen. A control respiratory frequency (f) of 30 breaths per min was set and a control tidal volume (VT) was chosen to achieve normocapnia. Cardiovascular measurements were made during normoxemia and hypoxemia (FIO2 0.10) 5 min after f or VT was changed to simulate a decrease, no change, or an increase in ventilation. During normoxemia, the level of ventilation had little effect on the measured cardiovascular variables. At control levels of ventilation, hypoxemia caused an increase in cardiac output that was due solely to an increase in stroke volume as heart rate decreased; blood pressure was unchanged. Increasing ventilation during hypoxemia did not augment cardiac output or alter blood pressure as compared with that observed at control levels of ventilation. Decreasing ventilation during hypoxemia, however, decreased cardiac output due to a profound bradycardia; blood pressure increased significantly. Our data provide evidence that the level of ventilation significantly influences the cardiovascular response to hypoxemia in young lambs.

Purine and pyrimidine metabolism and electrocortical brain activity during hypoxemia in near-term lambs.

Insufficient cerebral O(2) supply leads to brain cell damage and loss of brain cell function. The relationship between the severity of hypoxemic brain cell damage and the loss of electrocortical brain activity (ECBA), as measure of brain cell function, is not yet fully elucidated in near-term newborns. We hypothesized that there is a strong relationship between cerebral purine and pyrimidine metabolism, as measures of brain cell damage, and brain cell function during hypoxemia. Nine near-term lambs (term, 147 d) were delivered at 131 (range, 120-141) d of gestation. After a stabilization period, prolonged hypoxemia (fraction of inspired oxygen, 0.10; duration, 2.5 h) was induced. Mean values of carotid artery blood flow, as a measure of cerebral blood flow, and ECBA were calculated over the last 3 min of hypoxemia. At the end of the hypoxemic period, cerebral arterial and venous blood gases were determined and CSF was obtained. CSF from 11 normoxemic siblings was used for baseline values. HPLC was used to determine purine and pyrimidine metabolites in CSF, as measures of brain cell damage. Concentrations of purine and pyrimidine metabolites were significantly higher in hypoxemic lambs than in their siblings, whereas ECBA was lower in hypoxemic lambs. Significant negative linear relationships were found between purine and pyrimidine metabolite concentrations and, respectively, cerebral O(2) supply, cerebral O(2) consumption, and ECBA. We conclude that brain cell function is related to concentrations of purine and pyrimidine metabolites in the CSF. Reduction of ECBA indeed reflects the measure of brain damage due to hypoxemia in near-term newborn lambs.

Nicotine delays arousal during hypoxemia in lambs.

A decreased ability to arouse from sleep in response to arterial hypoxemia may lead to severe asphyxia and has been proposed as a mechanism of sudden infant death syndrome. Based on previous observations that nicotine exposure, a major environmental risk factor for sudden infant death syndrome, may impair hypoxic defense in neonates, we hypothesized that a short-term infusion of nicotine could impair hypoxic arousal through interference with oxygen-sensing mechanisms. Seven chronically instrumented unanesthetized lambs were studied at the age of 4.6 +/- 1.3 d during normoxia and acute hypoxia (0.1 fraction of inspired oxygen) for 5 min. Ventilation, transcutaneous Hb oxygen saturation, blood pressure, heart rate, and time to arousal were compared during a control saline infusion and during a 0.5 microg x kg(-1) x min(-1) nicotine infusion. Activity states, i.e. wakefulness and quiet sleep as well as arousal, were defined by EEG, nuchal electromyogram, and electrooculogram. Each lamb acted as its own control. Arousal from quiet sleep occurred significantly later during nicotine infusion compared with control (177 +/- 93 versus 57 +/- 41 s, p < 0.01) and at a lower transcutaneous Hb oxygen saturation (60 +/- 12 versus 79 +/- 12%, p < 0.01) (paired t test). The ventilatory response to hypoxia in wakefulness was similar during both conditions but was significantly attenuated in quiet sleep during nicotine infusion (p < 0.001, 2-way ANOVA repeated-measures design). Blood pressure and heart rate responses were similar during both conditions. These results suggest that a brief nicotine exposure blunts oxygen sensitivity in young lambs, a finding of potential relevance for sudden infant death syndrome.

Cardiovascular adjustments to acute hypoxemia superimposed on chronic hypoxemia in lambs

Cardiovascular responses to acute hypoxemia are in part mediated through adrenergic and chemoreceptor stimulation. In chronic hypoxemia the response to these stimuli may be blunted. Therefore, we determined whether the cardiovascular responses to acute hypoxemia superimposed on 3-4 wk of chronic hypoxemia were blunted in lambs with an experimental cardiac right-to-left shunt (combination of atrial septal defect and variable pulmonary stenosis). Cardiovascular variables and regional blood flows were determined during chronic hypoxemia and after acutely reducing the arterial oxygen saturation by increasing the cardiac right-to-left shunt. Arterial oxygen saturation decreased (65 +/- 7 to 40 +/- 7%, P < 0.001) and systemic blood flow increased (164 +/- 63 to 233 +/- 100 ml.min-1.kg-1, P < 0.01), maintaining systemic oxygen supply and oxygen uptake. Blood flow to the myocardium (P < 0.01), the adrenals (P < 0.05), and the brain (0.05 < P < 0.10) increased, and oxygen supply to these organs was maintained. Conversely, blood flow to the kidneys and the gastrointestinal tract was unaltered, so that oxygen supply to these organs was decreased. The responses to acute hypoxemia in chronically hypoxemic lambs were similar to those previously reported in normoxemic lambs. We conclude that the cardiovascular responses to acute hypoxemia in chronically hypoxemic lambs are not blunted.

Effect of increased whole blood viscosity on regional blood flows in chronically hypoxemic lambs.

In chronic hypoxemia blood flow and oxygen supply to vital organs are maintained, but to nonvital organs they are decreased. We measured organ blood flows (microspheres) and whole blood viscosity in 10 chronically hypoxemic lambs, with an atrial septal defect and pulmonary stenosis, and in 8 control lambs. Vascular hindrance (resistance/viscosity) was calculated to determine to what extent the effect of increased blood viscosity on organ blood flow was compensated for by a decrease in vascular tone. Arterial oxygen saturation was decreased (68 +/- 10 vs. 91 +/- 3%, P < 0.001), and both hemoglobin concentration (145 +/- 10 vs. 109 +/- 9 g/l, P < 0.05) and blood viscosity (4.4 +/- 0.6 vs. 3.6 +/- 0.6 mPa.s, P < 0.05) were increased in hypoxemic lambs. Systemic blood flow, oxygen supply, oxygen uptake, and blood pressures were not significantly different between hypoxemic and control lambs. Myocardial and cerebral blood flow was maintained in hypoxemic lambs, whereas renal, gastrointestinal, splenic, and thyroidal blood flows were at least 30% lower. Vascular hindrance was significantly decreased in the myocardium and tended to be lower in the brain of hypoxemic lambs, but in all other organs it was similar to that in control lambs. It is concluded that blood flow is redistributed in chronic hypoxemia in lambs; myocardial and cerebral blood flow is maintained, whereas blood flow to splanchnic organs, the kidneys, and the thyroids is decreased. The decreased blood flow to organs is a consequence of the increased whole blood viscosity.

Left ventricular oxygen and substrate uptake in chronically hypoxemic lambs.

Myocardial oxygen demand may be increased in chronically hypoxemic lambs because of their increased heart rate. Therefore, we determined whether left ventricular (LV) oxygen supply, oxygen uptake and oxygen demand were proportionally increased in 6-wk-old lambs, after 4 wk of hypoxemia (n = 15), as compared with control lambs (n = 14). In addition, we determined whether LV glucose, pyruvate, lactate, FFA and ketoacids uptake were altered in hypoxemic lambs, because of alterations in arterial glucose, pyruvate and lactate concentrations, that may occur in hypoxemia. Hypoxemia was induced by the combination of an atrial septal defect and pulmonary stenosis. Arterial oxygen saturation was decreased in hypoxemic lambs (67 +/- 8 versus 91 +/- 3%, p < 0.001), Hb concentration was increased, so that arterial oxygen concentration was similar in both groups of lambs. Myocardial mass (61 +/- 13 versus 44 +/- 9 g, p < 0.001) and total myocardial blood flow (117 +/- 36 versus 62 +/- 27 mL.min-1, p < 0.001) were increased, mainly due to right ventricular hypertrophy. LV oxygen demand, estimated by the rate pressure product (2072 +/- 465 versus 1467 +/- 358 kPa.beat.min-1, p < 0.001), and oxygen uptake (723 +/- 223 versus 556 +/- 184 mumol.min-1 x 100 g-1, p < 0.05) were proportionally increased in hypoxemic lambs. LV oxygen supply increased linearly with oxygen uptake (r = 0.96) in all lambs, by adjustments in LV blood flow, which was increased in hypoxemic lambs (168 +/- 41 versus 134 +/- 45 mL.min-1 x 100g-1, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Carotid, Not Aortic, Chemoreceptors Mediate the Fetal Cardiovascular Response to Acute Hypoxemia in Lambs

The fetal cardiovascular response to acute hypoxemia consists of a decrease in heart rate, a variable change in mean arterial pressure, and an increase in peripheral vascular resistance. This response is mediated by the arterial chemoreceptors. To determine whether chemoreceptors in the carotid artery or in the aorta mediate the fetal cardiovascular response to acute hypoxemia, we studied the response to acute hypoxemia in fetal lambs at 125 to 130 d of gestation after selective carotid (six fetuses) or aortic (five fetuses) denervation. One to 3 d after insertion of catheters, hypoxemia was induced by inflating a balloon occluder around the ewe's hypogastric artery or by giving the ewe 95% N2 and 5% O2 to breathe. The chemoreflex response was measured as decrease in heart rate per decrease in Hb O2 saturation. To validate our results, we also studied the response to chemical stimulation of the chemoreceptors by injection of sodium cyanide into the inferior vena cava. We found that carotid denervation abolished the heart rate and peripheral vascular resistance responses to hypoxemia but that aortic denervation did not. Responses after injection of sodium cyanide were similar to those seen during acute hypoxemia. We conclude that the carotid chemoreceptors, and not the aortic chemoreceptors, mediate the fetal cardiovascular response to acute hypoxemia.

Body fluid compartment volumes in chronically hypoxemic lambs.

Chronic hypoxemia is associated with a decreased growth rate and a decreased rate of cell division. In lambs with experimental cyanotic heart disease, the gain in body mass was decreased. In this study, we determined to what extent the lower body mass in these lambs was related to alterations in body fluid compartment volumes, specifically whether intracellular volume was decreased. Therefore, fluid compartment volumes were studied in nine lambs, after 3 to 4 wk of experimental cyanotic heart disease, and in 13 control lambs. Hypoxemic lambs had a lower arterial oxygen saturation (65 +/- 11 versus 91 +/- 2%, p < 0.001) and a higher Hb concentration (142 +/- 16 versus 101 +/- 8 g.L-1, p < 0.001). The lower body mass in hypoxemic lambs (10.5 +/- 2.3 versus 13.0 +/- 2.8 kg) could be mainly accounted for by a decrease in intracellular water volume (4.7 +/- 1.3 versus 6.6 +/- 1.5 L, p < 0.01). Total body water (753 +/- 27 versus 780 +/- 40 mL.kg-1) and extracellular water volume (307 +/- 25 versus 277 +/- 15 mL.kg-1) in hypoxemic lambs were not significantly different from those in control lambs, but intracellular water volume was decreased (445 +/- 27 versus 501 +/- 35 mL.kg-1, p < 0.01). The ratio of extracellular to intracellular water volume was higher in hypoxemic lambs (0.69 +/- 0.10 versus 0.55 +/- 0.04, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of atrial autonomic receptors in experimental cyanotic heart disease

During chronic hypoxemia, left ventricular beta-adrenergic receptor density is decreased and a dissociation occurs between increased chronotropic and decreased inotropic responses to chronically elevated sympathetic tone. To determine whether this dissociation was related to alterations in autonomic receptor populations in the right atrium, we studied right atrial cholinergic and beta-adrenergic receptors in chronically hypoxemic newborn lambs and in normoxemic controls. Heart rate response was determined by infusing isoproterenol at 0.1 or 0.5 microgram.kg-1.min-1. Muscarinic receptors were quantified with [3H]quinuclidinyl benzilate and beta-adrenergic receptors with [125I]iodocyanopindolol. Competition with ICI 118,551 was used to determine beta 1- vs. beta 2-receptor subtypes. In the hypoxemic lambs, isoproterenol resulted in a lesser percentage increase in heart rate (hypoxemic, 46 +/- 6% vs. control, 89 +/- 17%, P less than 0.05); however, because baseline heart rate was higher in the hypoxemic lambs (213 +/- 7 vs. 177 +/- 12 beats/min, P less than 0.05), maximal heart rate responses were similar (310 +/- 7 vs. 326 +/- 6 beats/min, NS). There was no change in receptor density or affinity of either muscarinic or beta-adrenergic receptors and no change in the proportion of beta 1- vs. beta 2-receptor subtypes. Thus the dissociation between the chronotropic and inotropic responses to chronic hypoxemia may be in part secondary to a differential regulation of beta-adrenergic receptors between the left ventricle and the right atrium.

Local cerebral glucose utilization in normoxemic and hypoxemic newborn lambs

To determine if hypoxemia altered local cerebral glucose utilization (LCGU) in newborn lambs, and where these alterations occurred, we measured LCGU using the 2-[ 14C]deoxyglucose ([ 14C]D-autoradiographic technique in lambs made hypoxemic by gradual reduction in inspired oxygen concentration. In 5 normoxemic control lambs, aged 3 days, LCGU of the cerebral cortex and white matter was higher than published values of LCGU in similar structures in near term normal fetuses and 2–4 times higher than reported values in normoxemic puppies. LCGU was highest in vestibular nuclei and auditory structures, followed by cerebellar nuclei, cerebral subcortical structures, and white matter. In 6 hypoxemic newborn lambs ( p a O 2 14–18 torr) consistent increases in LCGU were noted only in the corona radiata compared to the values obtained in the normoxemic control lambs (36.5 ± 8.1 vs. 23.9 ± 1.7 μmol/100 per min, mean ± S.D., P < 0.02). This increase in LCGU in white matter was clearly noted in autoradiographs in which thin dark central regions within white matter often reached high into the gyri. In the hypoxic group, LCGU of the corona radiata superseded the value in many gray matter structures. In addition, patchy increases of [ 14C]DG utilization were present in the cerebral cortex of two hypoxemic lambs. Acute hypoxemia increases glucose utilization of the corona radiata to values equivalent to many gray matter structures, and leads to heterogeneous glucose metabolism in the cerebral cortex, but does not alter LCGU in other gray matter structures of newborn sheep.

Influence of carotid denervation on the arousal and cardiopulmonary response to rapidly developing hypoxemia in lambs.

Experiments were done on five lambs to determine if carotid denervation influences the arousal and cardiopulmonary responses to rapidly developing hypoxemia during sleep. Each lamb was anesthetized and instrumented for recordings of electrocorticogram, electrooculogram, nuchal and diaphragm electromyograms, and measurements of arterial blood pressure and arterial hemoglobin oxygen saturation. The carotid chemoreceptors and baroreceptors were denervated, a tracheostomy was done, and a fenestrated tracheostomy tube was placed in the trachea so that the inspired oxygen mixture could be changed quickly. No sooner than 3 d after surgery, measurements were made in quiet sleep and active sleep during control periods when the animal was breathing 21% oxygen and during experimental periods of rapidly developing hypoxemia when the animal was breathing 5% oxygen. Rapidly developing hypoxemia was terminated during each epoch by changing the inspired gas mixture back to 21% oxygen once the animal aroused from sleep or once the arterial Hb oxygen saturation decreased to 30%. Arousal occurred during only 4 of 11 epochs in quiet sleep and during only 3 of 14 epochs in active sleep before the arterial IIb oxygen saturation decreased to 30%. These data provide evidence that the carotid chemoreceptors and/or carotid baroreceptors play a major role in causing arousal from sleep during rapidly developing hypoxemia in lambs.

126: THE ROLE OF OXYGEN AFFINIY IN THE ADAPTATION TO CHRONIC HYPOXEMIA IN 5-WEEK-OLD LAMBS

A decrease in oxygen affinity of hemoglobin could contribute to the adaptation to chronic hypoxemia in a right-to-left shunt. We studied P50, systemic oxygen delivery (SOD) and oxygen uptake (VO2) in the 6th week of life in 11 chronically hypoxemic and in 14 nonroxemic lambs. Hypoxemia had been experimentally induced in the 2nd week of life by means of an atrial septal defect and a pulmonary stenosis. Hypoxemic lambs had a decreased arterial oxygen saturation (66±7 vs 93±2 %, mean ± SD, p<0.001) and an increased hemoglobin concentration (145±14 vs 104±14 g.l−1,p<0.001). Heart rate was increased (171±28 vs 143±32 beats. min−1, p<0.05) but systemic blood flow (SBF) was not different Also SOD (23±10 vs 23±5 ml.min−1.kg−1) and the P50 were not different (5.03±0.43 vs 5.10±0.45 kPa). VO2 was maintained in hypoxemic lambs (9±3 vs 9±1 ml.min−1.kg−1) but mixed venous oxygen saturation (SmvO2) (41±9 vs 58±2 %, p<0.001) and oxygen tension (6.0±1.0 vs 7.2±0.5 kPa,p<0.001) were decreased. We conclude that P50 does not change in chronically hypoxemic lambs. These results suggest that the minimally attainable SmvO2 will be equal in hypoxemic and control lambs so the amount of oxygen that can be unloaded will be decreased in hypoxemia. We speculate that the ability to increase oxygen-extraction and SBF is limited in hypoxemia. This will impair the ability to meet increased demands for oxygen.

Effect of beta-adrenergic receptor blockade on responses to acute hypoxemia in lambs.

We studied the effects of beta-adrenergic receptor blockade on general circulatory and metabolic responses to moderate (FIO2 = 0.09) acute hypoxemia in newborn (protocol 1) and 3-wk-old (protocol 2) lambs, and on regional blood flow distribution in newborn lambs (protocol 1). Via a left thoracotomy we placed an electromagnetic flow transducer around the ascending aorta and inserted various vascular catheters. After 2 days of recovery, the lambs were studied. In protocol 1, we measured cardiovascular variables and regional blood flow distribution during control conditions, after 45 min of acute hypoxemia, and after 0.5 mg/kg of propranolol during acute hypoxemia. In protocol 2, we measured cardiovascular variables during control conditions and after 45 min of acute hypoxemia with and without propranolol pretreatment. In both groups, propranolol limited the increase in cardiac output and heart rate caused by hypoxemia, and thus decreased oxygen delivery. However, propranolol also decreased oxygen consumption so that pulmonary arterial pO2 was either higher (protocol 1) or the same (protocol 2) as during acute hypoxemia alone. Neither metabolic acidosis nor hypothermia ensued. In protocol 1, propranolol decreased renal, carcass, and most importantly, myocardial blood flows. However, myocardial O2 consumption also fell, coronary sinus pO2 increased, and blood was redistributed toward the subendocardium, suggesting that myocardial perfusion improved. Thus, beta-adrenergic receptor blockade during acute moderate hypoxemia may have a beneficial effect by reducing total body and myocardial oxygen demand in excess of the reduction in oxygen delivery.

Arousal from sleep during rapidly developing hypoxemia in lambs.

Arousal is an important protective response that may prevent severe hypoxemia and death during sleep. However, very little is known about arousal from sleep in response to respiratory stimuli in newborns. Experiments were therefore done to investigate the arousal response from sleep to rapidly developing hypoxemia in eight lambs. Each lamb was anesthetized and instrumented for recordings of electrocorticogram, electrooculogram, nuchal and diaphragm electromyograms, and measurements of arterial hemoglobin oxygen saturation. A tracheotomy was done and a tracheostomy tube placed in the trachea so that the fraction of inspired oxygen could be changed quickly. No sooner than 3 days after surgery, measurements were made in quiet sleep and active sleep (AS) during 30-s control periods when the animals were breathing 21% oxygen and during experimental periods of hypoxemia when the animals were breathing either 10, 5, or 0% oxygen in nitrogen. During quiet sleep, arousal occurred at similar arterial hemoglobin oxygen saturations (81 +/- 6% on 10% O2, 80 +/- 5% on 5% O2 and 83 +/- 5% on 0% O2) suggesting that arousal was independent of the rate of change of arterial oxygen. However, during AS arousal occurred at different arterial hemoglobin oxygen saturations (76 +/- 6% on 10% O2, 55 +/- 11% on 5% O2, and 44 +/- 17% on 0% O2) suggesting that arousal was dependent on the rate of change of arterial oxygen. During some epochs of AS, electrocortical signs of cerebral hypoxia and primary apnea occurred before arousal. These data provide evidence that arousal from quiet sleep in response to hypoxemia occurs once an arousal threshold has been reached.(ABSTRACT TRUNCATED AT 250 WORDS)

EXTRACELLULAR BODY FLUID VOLUMES IN CHRONICALLY HYPOXEMIC LAMBS

The extent to which body fluid volumes change as a consequence of chronic hypoxemia is not exactly known. Therefore we measured extracellular and plasma volumes in 5 chronically hypoxemic lambs. Before the 10th day of life we placed an inflatable balloon around the pulmonary artery, performed an atrial septostomy and inserted catheters. On days 3-4 after surgery the balloon was gradually inflated. In another 7 lambs only catheters were placed. At 5 weeks of age the lambs were studied. We used single injections of ferrocyanide and Evans blue to measure extracellular and plasma volumes, respectively.The hypoxemic lambs had a lower aortic oxygen saturation (69±9 (SD) vs 92±2%, p<0.01), and a higher hemoglobin concentration (142±17 vs 97±10 g.1−1, p<0.001) and hematocrit (43±5 vs 29±6%, p<0.01). Total extracellular fluid volume (320±31 vs 273±17 ml·kg−1 p<0.01) and blood volume (134±33 vs 80±12 ml·kg−1, p<0.05) were increased in hypoxemic lambs. This was also true for plasma volume (81±22 vs 58±5 ml·kg−1) and interstitial fluid volume (238±29 vs 215±18 ml·kg−1), although these differences did not reach statistical significance.These results show that total extracellular fluid volume and blood volume are both increased in hypoxic lambs, and that total hemoglobin mass is even more increased than the hemoglobin concentration would lead us to expect.

127 CHRONIC HYPOXEMIA IN THE 5-WEEK-OLD LAMB

The mechanisms involved in the adaptation to chronic hypoxemia, so as to maintain normal systemic oxygen delivery (SOD), are not quite clear. Therefore we studied these mechanisms by inducing chronic hypoxemia in 6 newborn lambs. We placed an inflatable balloon around the pulmonary artery after atrial septostomy, and inserted catheters. On days 3-4 after surgery the balloon was gradually inflated. In another 6 lambs only catheters were placed. At 5 weeks of age the lambs were studied. The hypoxemic lambs had a lower aortic and mixed venous oxygen saturation (60±10 (SD) vs 93±2, and 34±7 vs 58±2%, resp., p<0.001), and higher hemoglobin concentration (132±15 vs 101±10 g·1−1, p<0.002). Their P50 as well as their systemic blood flow were not significantly different. The heart rate of the hypoxemic lambs, however, was higher (205±22 vs 153±42, p<0.05). Although SOD in the hypoxemic lambs was lower than in the control lambs, this difference was not statistically significant (17.0±3.4 vs 21.2±5.9 ml.min−1kg−1). The mean weight gain of the hypoxemic lambs was lower (90±39 vs 153±34 g·day−1, p<0.02), while their oxygen consumption was the same as in the control lambs (7.0±2.2 vs 7.2±1.5 ml·min−1kg−1). These data show that to adapt to chronic hypoxemia the lamb increases its hemoglobin concentration to improve arterial oxygen content, and its heart rate to maintain cardiac output. We speculate that the costs of chronic hypoxemia, such as increased cardiac work, are probably effected at the expense of growth.

Chronic hypoxemia in the newborn lamb: cardiovascular, hematopoietic, and growth adaptations.

We have created a model of chronic hypoxemia in the newborn lamb by decreasing pulmonary blood flow in the presence of an atrial septal defect. Via a left lateral thoracotomy, we place an inflatable balloon around the pulmonary artery and perform an atrial septostomy under direct vision. We also insert several vascular catheters and place an electromagnetic flow transducer around the ascending aorta. Three days after surgery, we inflated the balloon in 11 lambs such that arterial oxygen saturation decreased to 60 to 75%. Studies were performed on these lambs twice weekly and weekly on 12 normoxemic lambs. Growth decreased sharply (47 +/- 123 versus 221 +/- 82 g/day) at the onset of hypoxemia and remained low, although oxygen consumption followed the normal gradual decline. Heart rate remained elevated throughout the study. Arterial PCO2 levels decreased from 40 +/- 5 to 35 +/- 7 torr and remained low. Systemic blood flow decreased at balloon inflation but quickly returned to normal. Mixed venous saturation was low, but could decrease further with shivering. Systemic oxygen delivery decreased initially but returned to normal as Hb concentration rose (from 9.4 +/- 1.5 to 12.5 +/- 2.2 g/dl). P50 increased normally over the study period. Four of the 11 hypoxemic lambs died during the study. These data show that, in the chronically hypoxemic newborn, systemic oxygen delivery is maintained primarily by a rising Hb. Total body oxygen consumption is maintained at rest but is redistributed away from anabolic requirements and toward cardiorespiratory work. This signal to decrease growth occurs despite less than maximal oxygen extraction at rest.

319 CHRONIC HYPOXEMIA IN THE NEWBORN LAMB

The adaptive mechanisms by which oxygen delivery is maintained during chronic hypoxemia, and the costs of such adaptations, are not well defined. In the newborn lamb, we have induced chronic hypoxemia by placing an inflatable balloon around the pulmonary artery after performing an atrial septostomy. Three days after surgery, the balloon was gradually inflated in 11 lambs to create a right-to-left atrial shunt such that arterial oxygen saturation was between 60 and 75%. Twice weekly studies were performed on these lambs and weekly studies on 12 normoxemic lambs. Growth decreased sharply (47 ± 123 vs 221 ± 82 g/day) at the onset of hypoxemia and remained low, although oxygen consumption followed the normal gradual decline. Systemic blood flow decreased at balloon inflation but quickly returned to normal. Mixed venous and coronary sinus saturations were low, but could decrease further with shivering. Systemic oxygen delivery returned to normal as hemoglobin concentration rose (from 9.4 ± 1.5 to 12.5 ± 2.2 g/dl). P50 did not change. Four of the 11 hypoxemic lambs died during the 2 week study period. These data show that systemic oxygen delivery is maintained primarily by rising hemoglobin in the chronically hypoxemic newborn. There is a signal to decrease growth apparently to maintain some reserve. The limited reserve is shown by a high mortality rate despite normal oxygen delivery at rest.