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As part of the Collaborative Home Infant Monitoring Evaluation (CHIME) we compared apnea identified by a customized home monitor using respiratory inductance plethysmography (RIP) with simultaneously recorded polysomnography-acquired nasal end-tidal CO2 (Pet CO2 ) and nasal/oral thermistor in 422 infants during overnight laboratory recordings to determine concordance between techniques, sources of disagreement, and capacity of RIP to detect obstructed breaths within an apnea. Among 233 episodes of apnea identified by at least one method as ⩾ 16 s, 120 were observed by the CHIME monitor, 219 by Pet CO2 , and 163 by thermistor. The positive predictive value of the CHIME-identified apnea was 89.2% (95% CI 83, 95) and 73% (95% CI 65, 81) for Pet CO2 and thermistor, respectively. However, the sensitivity of the CHIME monitor in identifying events detected by the other methods was only ∼ 50%. Among 87 apnea events identified by all three techniques, no two methods showed high agreement in measurement of apnea d...

Extracorporeal membrane oxygenation (ECMO) is a means of diverting a fraction or all of the circulation through a device that permits gas exchange across a permeable membrane. The site of removal and the site of return of blood are dictated primarily by practical considerations based on the volume of flow of blood to be diverted and whether a particular organ is to be bypassed. The prototype of extracorporeal oxygenation is heart-lung bypass, used for various types of cardiac surgery, in which the entire venous return is diverted through an oxygenator (bubble or membrane type) and returned to the aorta. Since the earliest reports of the use of ECMO in neonates, venoarterial bypass has been the preferred route, with blood drained from the right atrium and returned either to the carotid artery or to the femoral artery, although the former seems to have been used most often (2;4;11;12;14;18). In some reports, veno-venous bypass has also been accomplished with removal of blood from the right atrium and return into the umbilical or femoral vein (13;19). Gas exchange across the lung may also continue, although the ventilator rate, tidal volume, or peak inspiratory pressure are usually reduced markedly during the period of extracorporeal oxygenation. Anticoagulation is accomplished with few problems by infusion of heparin sulfate throughout the duration of the procedure. There now have been enough reports in the literature (individual cases or series of patients) to demonstrate that the procedure can be carried out with a minimum of technical difficulties in newborn infants (2;3;4;11;12;18), although the selection of “appropriate” patients reduces the morbidity and technical challenges of the procedure.

Persistent pulmonary hypertension of the newborn or persistent fetal circulation is a clinical syndrome that is usually apparent within the first 2 days after birth because of the presence of hypoxemia (2;12;19). The syndrome was first described in an abstract by Gersony, Due, and Sinclair (6) in 1969. Two infants were reported who had “RV decompensation, cyanosis and clear lung fields… in the absence of recognizable cardiac, pulmonary, hematologic or CNS disease.” The syndrome has been associated with aspiration of meconium, diaphragmatic hernia, asphyxia, hemorrhage, shock, and maternal infection (4;18). In other cases, there is no clear antecedent event. Despite considerable interest in the problem and a wealth of research related to pulmonary vasoregulation and vascular development in the fetus and newborn, the etiology of the syndrome remains obscure 20 years since its recognition.

We previously observed young lambs to be more tolerant of hypoxia; compared with older lambs, they accumulate lactate at a slower rate during comparable reduction in cardiac output, and have a greater percent decrease in cardiac output before onset of systemic lactate accumulation. To determine the mechanism of lactic acidosis and the cause for this "tolerance," we reduced cardiac output progressively in seven chronically catheterized conscious lambs (16.4 + 5.1 d) and measured hepatic and gastrointestinal (GI) blood flow (radioactive microspheres) and delivery, uptake, and extraction of lactate and O2. Hepatic O2 consumption declined proportionately below a critical hepatic O2 delivery (approximately 2 mL O2/min/kg), corresponding to the systemic O2 delivery associated with the onset of systemic lactate accumulation. As hepatic O2 delivery decreased below the critical value, there was initially net hepatic lactate uptake and then a change to net production when the O2 delivery decreased below approximately 1 mL O2/min kg. The GI tract had net lactate production at rest, but surprisingly switched to lactate uptake as cardiac output decreased. The mechanism of lactic acidosis was failure of hepatic lactate uptake to increase despite increased hepatic lactate delivery, as reported in adults subjects. However, in contrast, there was "true" hepatic dysfunction and lactate production only at the lowest levels of cardiac output, after onset of systemic lactate accumulation. Moreover, we speculate that tolerance of young lambs to hypoxia is at least due to two factors: 1) hepatic lactate uptake is maintained beyond the "critical" O2 delivery and fall in hepatic O2 consumption, and 2) there is a switch to lactate uptake by the GI tract serving to buffer the lactate.

We tested whether digoxin would limit tissue hypoxia during severe anemia by improving peripheral O2 distribution or decreasing O2 demands. Hematocrit (Hct) was reduced in eight control and eight digoxin-treated pigs from 27-28% to 17-18, 11-12, and 7-8%. Whole body and hindlimb blood flow, O2 transport, O2 extraction, and O2 consumption and serum catecholamines (epinephrine and norepinephrine) were determined at each Hct. Arterial and femoral venous lactate and O2 deficit were obtained to reflect tissue hypoxia. Cardiac output was significantly greater (P less than 0.05) with digoxin, as expected, but there were no differences in hindlimb blood flow. Also, whole body and hindlimb O2 extractions were equal in both groups for similar levels of O2 transport, suggesting that digoxin did not alter the relationship of O2 flow to metabolism in regional circulations. As whole body O2 consumption fell, controls accumulated more (P less than 0.05) O2 deficit and arterial lactate than the digoxin group. Furthermore, the slope demonstrating the linear increase of lactate with respect to O2 deficit was much steeper in controls (y = 1.11 + 0.06x) than in digoxin (y = 1.36 + 0.02x), suggesting that there were differences in the degree of tissue hypoxia for comparable O2 deficit. This may be attributed to the marked differences in catecholamine response: epinephrine was higher in controls at Hct of 7-8% and norepinephrine was higher at Hcts of 11-12 and 7-8%. Digoxin may have inhibited the release of catecholamine or reduced the stimulus for catecholamine secretion during anemia. We speculate that digoxin markedly improved the balance between peripheral O2 supply and demand during anemia by inhibiting catecholamine thermogenesis, thereby decreasing O2 demands. This may explain some of the salutary effects of glycosides in high-output cardiac failure with normal ventricular function.

The effect of physical training on the exercise performance of 26 patients following surgical repair of tetralogy of Fallot (16 patients) and ventricular septal defect (ten patients) was evaluated. Base line exercise testing was performed on a bicycle ergometer using the technique of Godfrey. Patients were placed on a six-week alternate day submaximal interval home exercise program of varying duration and intensity. Work loads at 50%, 60%, and 70% maximum oxygen consumption were selected to maintain heart rates between 130 and 160 beats per minute. Subjects completed an average of 18 of the possible 21 training sessions (range 11 to 21). A 25% improvement (P < .001) was noted in maximum work capacity (747 to 935 km). Sixty-five percent of the patients performed at less than expected maximum work capacity prior to training, but only 31% performed at less than expected maximum work capacity after training. Repeat testing at work loads of one-third, one-half, and two-thirds the original maximum work capacity revealed improved aerobic efficiency as manifested by significantly decreased oxygen consumption and heart rate at each level of work. No significant difference was noted in maximum oxygen consumption. It is concluded that physical training can improve the exercise performance of patients after surgical repair, permitting the individuals to function at levels of activity at, or closely approaching, normal.

We studied the effects of anemia and ouabain administration on cardiac function, oxygen physiology, and blood catecholamine levels in nine newborn lambs. We measured oxygen consumption continuously, along with traditional hemodynamic variables. Oxygen transport was calculated. Following baseline measurements, lambs were made anemic (mean hematocrit = 12%) by isovolemic exchange transfusion with Plasmanate, and measurements were repeated. Thereafter ouabain was administered as a 75 micrograms/kg bolus, followed by 30 min of infusion at a rate of 0.05 microgram/kg/min. Measurements were repeated at the conclusion of infusion. Anemia was associated with a heart rate related rise in left ventricular rate of pressure rise, a rise in oxygen consumption, an increase in cardiac output, a decrease in systemic vascular resistance, and a rise in fractional oxygen extraction (oxygen consumption/transport). Following ouabain administration, cardiac output, oxygen consumption, and stroke work fell, but left ventricular rate of pressure rise and the extraction ratio did not change. Serum levels of epinephrine and norepinephrine rose with sustained anemia and ouabain infusion. In this setting, ouabain effects are manifested primarily by alterations in oxygen transport and metabolism rather than by changes in traditional assessments of left ventricular contractile function.

A 15-year-old boy with diarrhea, dizziness, dysesthesias, and depression is described. On admission, his blood pressure was 110/84 reclining but less than 40 systolic while standing. Vibratory sensation and nerve conduction velocities were decreased in his lower extremities. CSF protein concentration was normal but sural nerve biopsy demonstrated generalized demyelination. Extensive toxicologic and metabolic screening proved unremarkable. Norepinephrine concentrations in plasma and urine, and CSF concentration of 3-methoxy-4-hydroxy phenylglycol (MHPG) were markedly reduced. The patient demonstrates a combination of autonomic dysfunction, peripheral neuropathy, and affective disorder. This collection of clinical and neurochemical findings represents a previously unreported entity involving a defect of both central and peripheral noradrenergic systems.

We previously found limited tolerance to acute reduction in cardiac output in lambs at the nadir of their physiological anemia [Am. J. Physiol. 253 (Heart Cir. Physiol. 12): H100-H106, 1987]. To determine the effect of hemoglobin concentration [Hb] on critical cardiac output, critical systemic O2 transport, and peripheral O2 extraction, we performed 31 experiments in 12 one-mo-old lambs at four [Hb] (means +/- SD in g/dl): 7.4 +/- 0.6, 10.5 +/- 0.5, 14.5 +/- 0.5, and 16.5 +/- 0.6. Desired [Hb] was obtained by exchange transfusion with packed red cells or plasma. Cardiac output was reduced by inflation of a balloon-tipped catheter in the right atrium, and critical levels were defined at the point where O2 consumption decreased and/or arterial blood lactate concentration increased in response. With lower [Hb], cardiac output was unchanged, systemic O2 transport was reduced, and fractional O2 extraction was increased, keeping O2 consumption constant at base line. As [Hb] was reduced, critical cardiac output was significantly higher, whereas critical systemic O2 transport was independent of [Hb], as were fractional O2 extraction and mixed venous PO2 at the critical point. Thus peripheral O2 extraction was not affected by changes in [Hb] during progressive decreases in cardiac output. We conclude that 4-wk-old lambs have decreased tolerance to reductions in cardiac output and systemic O2 transport because their relative anemia provides them with a base-line cardiac output and systemic O2 transport close to the critical level.

Angiotensin-converting enzyme (ACE) activity of the cerebral microcirculation of anesthetized dogs was measured from cerebral venous outflow curves after bolus injection of a synthetic ACE substrate, [3H]benzoyl-phenylalanyl-alanylproline ([3H]BPAP), into a common carotid artery. Cerebral BPAP metabolism was quantified by measuring the concentration of [3H]benzoyl-phenylalanine (the product of BPAP hydrolysis by ACE) in blood samples from the sagittal sinus after occlusion of the lateral sinuses with bone wax. Instantaneous BPAP metabolism in each sample increased as a function of time after injection, suggestive of perfusion heterogeneity, and averaged 59 +/- 4% (n = 8) over a single pass during normoxia and normocapnia. The ratio of Vmax (the maximal rate of cerebral BPAP metabolism) to Km (the concentration at Vmax/2), was calculated from instantaneous outflow curves using a model based on first-order kinetics. Increases in cerebral blood flow during either hypoxia or hypercapnia significantly reduced BPAP metabolism to 33 +/- 3 (n = 7) and 24 +/- 3% (n = 5), respectively; however, Vmax/Km of ACE activity (0.19 +/- 0.03 ml/s) was not affected by either condition. The lack of change in apparent kinetics of ACE activity (i.e., in Vmax/Km) during hypoxia or hypercapnia suggests that recruitment of cerebral capillaries was not a quantitatively significant factor in controlling BPAP metabolism with this degree of either hypoxia or hypercapnia.

We measured cardiac output and its distribution (microspheres), blood gases and pH, heart rate, and pulmonary and aortic pressures in three groups of 1- to 3-day-old lambs. Group I consisted of six animals who had these measurements made during both control (normoxemic) and hypoxemic (PaO2 25 +/- 3 mm Hg) periods. Hypoxemia increased the pulmonary artery pressure 70% (p less than 0.01). This elevation in pulmonary arterial pressure lasted as long as the animals were hypoxemic (90 min). Hypoxemia had no effect on cardiac output, mean systemic arterial pressure, heart rate, or the rate-pressure product of the left ventricle. Blood flow to the heart increased an average of 228% (p less than 0.05); flow to the brain increased 233% (p less than 0.05); flow to the skin decreased 35% (p less than 0.05) after 60 and 90 min of hypoxemia. Blood flow to the remaining organs was uneffected by hypoxemia. Group II consisted of four animals who were given 1, 5, and 10 mg/kg/h of tolazoline (Priscoline) intravenously while normoxemic. There was no effect on the pulmonary arterial pressures or blood gases and pH. Tolazoline (5 and 10 mg/kg/h) reduced systemic arterial pressures an average of 22% (p less than 0.05). Tolazoline (1 mg/kg/h) reduced blood flow to the spleen 48% and that to the brain by 20% and increased flow to the body 32% (p less than 0.05). Five mg/kg/h of tolazoline decreased renal and brain blood flow 35 and 20%, respectively (p less than 0.05) while that to the body and liver increased 26 and 48% (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

When cardiac output is critically lowered, whole body O2 consumption decreases and an O2 deficit accumulates. With restoration of cardiac output, an excess 02 consumption is expected in order to "repay" some or all of the O2 deficit. We tested the hypothesis that young lambs, with higher resting O2 consumption, cardiac output and growth rates than older lambs, would repay less of their 02 deficit because they have a higher proportion of nonessential metabolism. We reduced cardiac output acutely by inflating a Foley catheter in the right atrium of spontaneously breathing, sedated lambs at ages 2 (n = 5) and 8 (n = 5) wk. Each lamb was studied with low cardiac output periods of 30 and 60 min on different days. Aortic and pulmonary artery blood pressures, gases, and O2 sat- urations, venous Hb, and arterial lactate concentrations were measured every 10 min during baseline, low output, and 60 min of recovery. Oxygen consumption was moni- tored continuously. Oxygen deficit and excess O2 of recov- ery were calculated from the time integral of the difference between O2 consumption at baseline and during the re- spective study period. The average percent decreases in cardiac output (66.4 and 64.6%) and 02 consumption (38.1 and 35.1%) were similar in the 2- and 8-wk groups, re- spectively. There was no consistent relation between 02 deficit and O2 repayment in either age group. However, on average the 2-wk group repaid a significantly lower per- centage (3 f 16%, mean f SEM) than 8-wk-olds (76 k 29%). Moreover, lactate increased linearly with time and O2 deficit in both age groups, but lactate accumulated at a significantly lower rate in the 2-wk as compared to the 8- wk group for comparable deficits. We speculate that, dur- ing periods of very low cardiac output, 2-wk-old lambs not only decrease O2 consumption, but also decrease metabolic demands, possibly by suppressing nonessential metabo- lism. This results in fewer energy stores that need to be replenished during recovery. This is a potential mechanism for the greater tolerance of young animals to hypoxic stresses. (Pediatr Res 26: 180-187, 1989)

T HE TRANSPORT of oxygen (0,) from the environment to the cells of the body tissues depends on the capability of three organ systems.“’ The lungs must be able to take up 0, from the environment and add,it to venous blood in order to maintain arterial O2 concentration at acceptable levels. The blood must be able to bind and release OZ. The circulatory system must be able to maintain adequate tissue blood flow. These three systems act together in an integrated fashion to adapt, both acutely and chronically, to changes in tissue O2 demands by altering O2 delivery. In addition, each organ system may act individually in a compensatory fashion to make up for deficiencies in O2 delivery should either of the other systems fail.3 It is the aim of this review to focus specifically on disruptions in 0, delivery consequent to limitations in blood flow. We first discuss the experimental observations that have described the local and systemic responses and metabolic consequences of a low cardiac output and then try to relate these findings to the understanding of patients with inadequate systemic perfusion.

The major attempt in this monograph has been to provide a systematic approach to OT in the infant under normal and abnormal conditions based on an appreciation of pathophysiologic mechanisms. This has included a consideration of oxygen uptake, gas transfer from the lungs to the circulation, oxygen delivery to the tissues, and various adaptive responses. We have discussed disorders involving the control of respiration, the upper and lower airways, lung parenchyma, pulmonary circulation, heart, and the oxygen carrier, hemoglobin, that may impair OT to tissues, and how compensation for these conditions can be achieved. The clinical presentation in each of these pathologic processes represents the net effect of the lesion on the multiple steps involved in the transport of oxygen to the tissues and the adaptation provided by the lungs, heart, circulation, and hematologic system. These must be taken into account in developing a plan for medical and/or surgical treatment that is focused on improving the supply of oxygen to the various organ systems of the body.

Although a considerable amount of information is available regarding the remodeling and growth of the pulmonary arterial circulation, relatively little is known regarding postnatal development of the pulmonary microcirculation. We hypothesized that the maximal velocity (Vmax) of pulmonary angiotensin-converting enzyme (ACE) activity, measured from indicator-dilution outflow curves using a synthetic substrate, 3H-labeled benzoyl-phenylalanyl-alanyl-proline (BPAP), is directly related to the capillary endothelial cell surface area in the lungs of developing lambs. Accordingly we measured apparent kinetics of pulmonary ACE activity in 22 anesthetized ventilated lambs (2–171 days old) and compared our functional assessment to simultaneous in vivo determinations of CO diffusing capacity (DLCO) and postmortem structural assessment of alveolar septal dimensions using stereology and electron microscopy. There was a progressive increase in Vmax of ACE in this age group, with little change in apparent affinity for BPAP. Similar functional manifestation of growth was noted by an age-dependent increase in DLCO. Neither Vmax nor DLCO was significantly affected by an increase in left atrial pressure to 19 Torr (via inflation of a balloon in the left atrium), suggesting little recruitment of vessels under conditions of the present protocol. A close correlation was observed when either Vmax for ACE activity or DLCO was plotted vs. capillary endothelial cell surface area. Double logarithmic transformation of capillary endothelial cell surface area, Vmax-ACE and DLCO vs. lung volume revealed power functions with slopes all greater than that predicted from isotropic growth, suggesting selective differential postnatal development of the endothelium of the alveolar septum in lambs from 2–171 days of age.

We studied the acute effects of increasing hemoglobin concentration and hematocrit on the pulmonary and systemic circulations of nine infants with large left-to-right shunts. After isovolemic exchange transfusion, which was designed to raise hemoglobin but keep blood volume constant, a consistent rise in systemic and pulmonary vascular resistances occurred. This rise was comparable to those previously found in isolated circulations showing a linear relation between hematocrit and loge of the vascular resistance. These changes in resistance were accompanied by decreases in systemic and pulmonary blood flow and a marked decline in left-to-right shunt. Despite the decrease in systemic blood flow, there was no decline in systemic oxygen transport, and there may have been a marginal decrease in left ventricular stroke work. These observations help explain why the newborn with a large ventricular septal defect and a high hemoglobin concentration does not have clinical signs of a large left-to-right shunt, and also suggest that the postnatal decline in hematocrit has a substantial role in the normal fall in pulmonary vascular resistance after birth.

We studied the response of O2 consumption, systemic O2 transport, arterial blood lactate concentration, base deficit, and respiratory exchange ratio (CO2 production/O2 consumption) to graded alveolar hypoxia (fractional concentration of inspired oxygen 0.21, 0.16, 0.12, and 0.08) in seven intact, conscious chronically catheterized lambs at less than 1 wk after birth, at 25-40 days and at greater than 40 days. To test whether there was an age related difference in the metabolic response to a decline in O2 transport due to hypoxemia, we related the changes in blood lactate and base deficit to the systemic O2 transport and to the fractional change in O2 consumption. Systemic O2 transport and O2 consumption decreased with severe hypoxemia, while lactate concentration and respiratory exchange ratio increased in all age groups. The changes in base deficit were not significant. When the hypoxemia-induced reduction in O2 consumption was less than 15% of the baseline value (at fractional concentration of inspired oxygen 0.21) there was no elevation in lactate concentration; however, when O2 consumption was reduced by more than 15%, lactate concentration consistently increased by more than 1 mmol/liter. There were no apparent differences amongst the age groups in this response. Therefore, the newborn lamb does show metabolic consequences of a fall in O2 consumption with hypoxemia which is similar to the older sheep, however, there is a "buffer zone" in which O2 consumption may decrease before evidence of tissue hypoxia can be found. The mechanism by which O2 consumption can decrease without accumulation of lactate remains speculative.

This study was designed to determine whether alterations in systemic oxygen transport induced by the use of vasodilators for pulmonary hypertension would simultaneously affect oxygen uptake in patients with chronic obstructive pulmonary disease (COPD). Six stable patients with moderate to severe COPD were studied during resting conditons, nitroprusside infusion, a second control period, and after administration of hydralazine. Systemic oxygen transport fell with nitroprusside infusion (523 ± 94 to 418 ± 78 ml/min/m2, p < 0.05). With this there was a fall in oxygen uptake (135 ± 11 to 119 ± 12 ml/min/m2, p < 0.05), but only a minimal increase in oxygen extraction. In contrast, systemic oxygen transport was augmented in all patients when hydralazine was administered (444 ± 121 to 840 ± 157 ml/min/m2, p < 0.05). There was also a net increase in oxygen uptake in these patients (122 ± 19 to 148 ± 21 ml/min/m2, p < 0.05). We postulate that these clinically stable patients have a resting oxygen uptake that may b...

The observation has been made in the newborn (NB) animal that a fall in VO2 with alveolar hypoxia is not always accompanied by acidosis, suggesting that there is primarily a reduction in non-essential oxidative metabolism. To test this hypothesis we compared the metabolic consequences of an induced reduction in VO2 in conscious NB and older lambs. Seven lambs with chronic aortic and pulmonary arterial catheters were studied at < 7 days, at 1 mo. and at 2–3 mos. Sequential measurements were made at FIO2 = .21, .16, .12 and .08 obtaining: arterial and mixed venous blood gases, hemoglobin (Hb) concentrations, %HbO2, lactate (L), VO2, and CO2 production (VCO2). Base deficit (BD), cardiac output, systemic O2 transport (SOT) and R (VCO2/VO2) were calculated. All data were compared to measurements at FIO2 .21. In all groups when SOT fell sufficiently with hypoxia there was a fall in VO2. This occurred at a higher SOT in the NB (15 mlO2/min/kg) than lambs 2–3 mos (10 ml)2/min/kg). Δ L (L-L@control) consistently increased at all ages to ≥ 3 mMol/L whenever V)2 decreased to ≤ .7 × control VO2. Like L, BD and R increased significantly with a fall in VO2. Therefore we found that a comparable decrease in VO2 is attended by evidence of anaerobic metabolism at all ages; the major age related difference was the higher critical SOT at which this occurred in the newborn. Thus, the newborn does not seem to be less susceptible than the older subject to the impairment of oxidative metabolism caused by alveolar hypoxia.