Sex differences in fitness and cardiac function during exercise in adolescents with chronic fatigue.

Females demonstrate less robust Frank-Starling mechanism with respect to cardiac preload than males at rest. We asked whether this phenomenon would also affect cardiac performance during exercise. We hypothesized that stroke volume (SV) response to exercise would be more limited in deconditioned females such that cardiac output would be mainly rate dependent, compared with males. We conducted a chart audit of clinical exercise tests performed by adolescents with chronic fatigue. Oxygen uptake (V˙O2) was measured breath-by-breath at rest and during cycle ergometry, while cardiac output was measured by acetylene rebreathing at rest plus 2-3 subthreshold workloads. SV response was analyzed in two ways: after normalization for body surface area (SV index, SVI) and as percentage change from resting values. Among 304 adolescents (78% females) with chronic fatigue, 189 (80%) of 236 females and 52 (76%) of 68 males were deconditioned (peakV˙O2 <90% predicted). Heart rate trajectory during exercise was steeper for unfit than fit females, 70 vs 61 beat·min-1 per L·min-1 V˙O2, (P=.003); but not for males, 47 vs 42 beat·min-1 per L·min-1 V˙O2 (P=.23). The highest measured SVI did not differ between unfit vs fit females (42.8 vs 41.5 mL·m-2 , P=.39) while fit males showed larger SV during exercise than their unfit peers (highest SVI 55.9 vs 48.0 mL·m-2 , P=.014). Both qualitative and quantitative sex differences exist in SV responses to exercise among chronically fatigued adolescents, suggesting volume loading may be more efficacious in girls.

Airway resistance variability and response to bronchodilator in children with asthma.

Variability of airway function is a feature of asthma, spanning timescales from months to seconds. Short-term variation in airway resistance (R(rs)) is elevated in asthma and is thought to be due to increased variation in the contractile activation of airway smooth muscle. If true, then variation in R(rs) should decrease in response to bronchodilators, but this has not been investigated. Using the forced oscillation technique, R(rs) and the variation in R(rs) from 4-34 Hz were measured in 39 children with well-controlled mild-to-moderate asthma and 31 healthy controls (7-13 yrs) before and after an inhaled bronchodilator (200 microg salbutamol) or placebo. In agreement with other findings, baseline R(rs) at all frequencies and the sd of R(rs) (R(rs) sd) below 14 Hz were found to be elevated in asthma while neither forced expiratory volume in one second nor the mean forced expiratory flow between 25 and 75% of forced vital capacity were different compared with controls. The present authors found that R(rs) sd changed the most of any measurement in asthma, and this was the only measurement that changed significantly more in children with asthma following bronchodilator administration. The present results show that like airway narrowing, short-term airway variability of resistance may be a characteristic feature of asthma that may be useful for monitoring response to therapy.

Peak oxygen uptake and mortality in children with cystic fibrosis.

BACKGROUND: Single measurements of peak oxygen uptake (VO2) have been shown to predict mortality in patients with cystic fibrosis (CF) although no longitudinal study of serial measurements has been reported in children. A study was undertaken to determine whether the initial, final, or the rate of fall of forced expiratory volume in 1 second (FEV1) or peak VO2 was a better predictor of mortality. METHODS: Twenty eight children aged 8-17 years with CF performed annual pulmonary function and maximal exercise tests over a 5 year period to determine FEV1 and peak VO2, magnitude of their change over time, and survival over the subsequent 7-8 years. Analysis was done using Kaplan-Meier curves and Cox proportional hazard model. RESULTS: Peak VO2 fell during the observation period in 70% of the patients, with a mean annual decline of 2.1 ml/min/kg. Initial peak VO2 was not predictive of mortality but rate of decline and final peak VO2 of the series were significant predictors. Patients with peak VO2 less than 32 ml/min/kg exhibited a dramatic increase in mortality, in contrast to those whose peak VO2 exceeded 45 ml/min/kg, none of whom died. The first, last, and rate of decline in FEV1 over time were all significant predictors of mortality. CONCLUSIONS: Higher peak VO2 is a marker for longer survival in CF patients.

Cardiopulmonary exercise performance in prematurely born children.

Prematurely born children have reduced peak VO2 compared with their peers, inferentially attributed to ventilatory limitation. The primary purpose of this study was to compare exercise ventilation and cardiac output in a sample of childhood survivors of lung disease of prematurity with those of a control group to elucidate reasons for lower peak VO2. A secondary aim was to describe and compare the ventilatory response to incremental exercise. Thirty-two children, aged 8-9 y, were recalled for lung function and progressive exercise tests. Fifteen of them also performed submaximal exercise with measurement of cardiac output (indirect [CO2] Fick) and physiologic dead space. Results were compared with those of term-born, age- and sex-matched, control children. Pulmonary function tests showed mild airflow limitation. Peak VO2 was lower in prematurely born children compared with control children, and was correlated with lean body mass. Their heart rate-VO2 relationship and stroke volume were similar to that of term-born control children. Children with a history of bronchopulmonary dysplasia and hyaline membrane disease as infants exhibited greater exercise hyperpnea than did healthy control children, because of higher breathing frequency, and maintained lower end-tidal PCO2 during submaximal exercise. Physiologic dead space normalized for body weight was similar in preterm and term-born children. Lower peak VO2 in this population is not caused by cardiopulmonary factors, but is best predicted by lean body mass. Ventilation did not limit exercise performance, although it appears that breathing during exercise is regulated differently in prematurely born children than in term-born children.

High frequency ventilation trial. Nine year follow up of lung function.

The high frequency ventilation (HIFI) trial for hyaline membrane disease (HMD) showed no advantage of high frequency over conventional ventilation in pulmonary outcomes after 24 months. The present study tested the hypothesis that there would be no significant difference in childhood lung function between patients who had been ventilated by either method. Thirty-two children aged 8-9 years who completed the HIFI trial were asked to return for pulmonary function tests. For purposes of analysis, the patient population was divided according to mode of ventilation, and by diagnosis of bronchopulmonary dysplasia (BPD) or HMD. Results were compared to those of 15 term-born, matched, controls. Lung function tests showed a mildly obstructive pattern in prematurely born children. More severe obstruction was seen in those children who had physician-diagnosed asthma or who had used bronchodilators in the past. The prevalence of mild obstructive pattern on pulmonary function testing in preterm infants with HMD or BPD was similar in those who received high frequency vs. conventional ventilation. Factors other than the mode of ventilation exert greater influence on pulmonary outcome in survivors of lung disease of prematurity.

Pulmonary function following blastomycosis in childhood.

In order to determine the pulmonary outcome following blastomycosis during childhood, we compiled a case series of hospitalized patients from a retrospective review with later recall for pulmonary function testing, coupled with prospective measurements of pulmonary function in three patients, at a tertiary care children's hospital. A convenience sample of five of 17 patients hospitalized with pulmonary blastomycosis, whose mean age at the time of diagnosis was 10.6 +/- 5.5 years, was recalled at a mean of 4.5 +/- 3.5 years after diagnosis. Three patients more recently hospitalized underwent serial pulmonary function testing (PFT) prospectively from as soon after the acute infection as their condition permitted. All but two patients had normal PFT when last seen. The two patients with persistent pulmonary sequelae were among those followed up prospectively and had more severe clinical and radiographic pictures at the outset. Pulmonary function in children who suffered from pulmonary blastomycosis is normal in most patients at follow-up years later. Severe radiographic disease and slow recovery over months portend long-term sequelae.

Impedance cardiography accurately measures cardiac output during exercise in children with cystic fibrosis.

OBJECTIVES: After validation of impedance cardiography (ICG) in healthy children, this same device was tested in children with cystic fibrosis (CF) to validate its capability of measuring cardiac output (Q) in this population. DESIGN: Comparative study of ICG vs the indirect Fick (CO2) method. SETTING: Tertiary care children's teaching hospital. PATIENTS: Twenty-one CF children with mean FEV1 of 77 +/- 21% predicted. MEASUREMENTS: ICG results were compared with CO2 rebreathing (RB) measurements of Q with sampling of capillary blood gases at two levels of exercise (0.5 and 1.5 W/kg). ICG measurements were made each minute, and duplicate RB measurements from 6 to 8 min at each workload. Q was regressed against oxygen uptake and results by each method were compared. RESULTS: Mean bias (QRB-QICG) was -0.09 +/- 0.94 L/min. The largest deviation of QICG from QRB was +33%, and 83% of corresponding QICG values were within +/-20% of QRB result. CONCLUSIONS: This device gives rapid, accurate, noninvasive Q measurements in children with CF.

Carbon dioxide chemosensitivity and exercise ventilation in healthy children and in children with cystic fibrosis.

This two-part study sought to determine the relationship between arterial PCO2, CO2 chemoresponsiveness, and ventilation during exercise in healthy children and children with cystic fibrosis (CF). In the first part, we measured the hypercapnic ventilatory response (HCVR) in 16 healthy children and 16 patients with CF, and compared HCVR with the ventilatory response to progressive exercise (delta VE/delta VCO2). In the second part, we assessed the relation between age, the ventilatory equivalent for CO2 (VE/VCO2), and arterialized capillary PCO2 (PaCO2), during exercise in 28 healthy children and 23 children with CF. The HCVR showed an age-related decline in both healthy controls and CF subjects. In addition, there was a correlation between forced expiratory flow from 25 to 75% of forced vital capacity and the HCVR, regardless of age. In controls, but not in CF, there was also a decline in delta VE/delta VCO2 with increasing age; and there was a significant correlation between delta VE/delta VCO2 and HCVR. Findings in the second part were similar, with a significant inverse correlation between age and VE/VCO2 during steady state exercise only in healthy controls. However, when physiologic dead space was taken into account, both CF and healthy control children showed a significant decline in VA/VCO2 with age. When all subjects were grouped together, there was a statistically significant correlation between PaCO2 and age, such that younger subjects had lower PaCO2 than older subjects. Age and PaCO2 together accounted for 71% of the variance in VA/VCO2. We conclude that younger children ventilate proportionately more on exercise than older children because they regulate PaCO2 about a lower set point. As the ventilatory response to exercise is significantly correlated with the HCVR, and the latter can be reduced in the presence of airways obstruction, an innately low HCVR could permit the development of exertional hypercapnia in some CF patients with advancing pulmonary disease.

End-tidal estimates of arterial PCO2 for cardiac output measurement by CO2 rebreathing: a study in patients with cystic fibrosis and healthy controls.

We set out to determine the effects of various estimates of arterial PCO2 (PaCO2) on calculation of cardiac output (Q) by the indirect Fick (CO2) method in healthy children and children with cystic fibrosis (CF), and to develop a prediction equation for children for PaCO2, based on end-tidal PCO2 (PetCO2). The study had 3 parts: 1) Twenty-three healthy children exercised lightly and moderately while arterialized capillary blood gases and PetCO2 were measured simultaneously so that a prediction equation for PaCO2 could be derived from PetCO2. Cardiac output was measured by CO2 rebreathing at each workload; different values for PaCO2 (measured in arterialized capillary blood, end-tidal, and PaCO2 derived from the Bohr equation assuming normal dead space) were used to calculate Q; 2) our equation PaCO2 = 0.647 PetCO2 + 12.4 was tested prospectively to measure Q in 9 healthy children; and 3) cardiac output based on arterialized capillary PaCO2 was compared with that based on Jones-corrected PetCO2 during light and moderate exercise in 16 CF patients whose forced expiratory volume in 1 second (FEV1), range from normal to 37% predicted. Our results have shown that in healthy children end-tidal based-estimates of PaCO2 tended to overestimate Q, whereas PaCO2 values derived by the Bohr equation and assuming normal dead space tended to underestimate Q, compared with Q calculated from directly measured PaCO2. Our prediction equation resulted in good agreement compared with directly measured PaCO2 when used to calculate Q (mean difference, +1.3%; range, +9% to -13%). CF patients with little or no airway obstruction had results similar to healthy controls, but those with severe airway obstruction had lower values for Q when PetCO2 was used instead of directly measured PaCO2. We conclude that estimates of PaCO2 from PetCO2 are not reliable in patients with moderately severe pulmonary disease due to CF. In healthy children, the prediction equation for PaCO2 from PetCO2 derived in the present study gives results superior to other bloodless methods currently in use for computation of Q by the indirect Fick (CO2) method.

Comparison of impedance cardiography with indirect Fick (CO2) method of measuring cardiac output in healthy children during exercise.

Electric bioimpedance has been used to measure cardiac output for decades. Improvements in modeling and microprocessor technology have spawned newer generations of such devices. This method would be especially useful in children, in whom the use of invasive methods is limited. We tested a device (ICG-M401, ASK Ltd.) in 30 healthy children at 2 levels of exercise (0.5 and 1.5 W/kg), and compared impedance measurements of cardiac output (QICG) with carbon dioxide (CO2) rebreathing measurements of cardiac output (QRB). The QICG-oxygen uptake (VO2) rel ation was expressed by QICG = 3.8 + 4.6 VO2; r(2) = 0.68. Mean +/- SD bias (QICG-QRB) was 0.14 +/- 1.05 L/min, not significantly different from zero (95% confidence interval -0.12 to +0.44 L/min). All QICG results were within +/- 15% of the hypothetical mean value (Bland and Altman analysis). The largest deviation of QICG from QRB was +30%, found in 1 of 57 paired determinations. Eighty percent of QICG values were within +/- 20% of the QRB result. We conclude that impedance cardiography with the ICG-M401 provided realistic and reliable estimates of cardiac output in healthy children during exercise. This, along with its ease of operation and utility at rest and during exercise, make it both useful and attractive for clinic and research purposes.

Stroke volume during exercise in cystic fibrosis.

Previous studies comparing cardiac output (Q) and stroke volume (SV) between cystic fibrosis (CF) patients and control subjects have shown conflicting results: some found lower SV in CF patients with severe airflow limitation, and others showed no difference between CF and control subjects. Methodologic problems could explain these discrepant findings. The aim of this study was to better characterize Q and SV with exercise in CF patients with mild as well as severe airflow obstruction. Subjects included 18 CF patients with FEV1 ranging from 28 to 80% of predicted without pulmonary hypertension, and 16 matched control subjects. Cardiac output was measured at three levels of upright cycle exercise using the indirect Fick (CO2) method with blood gas sampling. Q on exercise was similar among control and CF subjects. SV was lower in CF patients, particularly those with FEV1 < or = 55% predicted, than in control subjects. Stepwise regression of SV on height, percent ideal body weight, and FEV1 showed a significant effect of relative underweight on SV. Despite this, well-nourished patients with FEV1 56 to 80% of predicted also had lower SV. As these findings were consistent across the range of severity of lung disease and age, even in the absence of malnutrition, they imply that another mechanism accounts for SV limitation during exercise in CF.

Hypoxic response is inversely related to degree of exercise hyperventilation.

The Dejours hyperoxic test has been used to quantitate peripheral chemoreceptor contribution to the hyperpnea of exercise. The strength of this drive, measured by the percent reduction in ventilation, varies among individuals and is lacking in chemodenervated humans, who also fail to manifest a hyperventilatory response in heavy exercise. We reasoned that greater hyperventilation in exercise above the anaerobic threshold ought to be associated with greater hypoxic (carotid body) drive. The present study tested this hypothesis. In 17 naive subjects, carotid body O2 chemosensitivity was tested repeatedly during exercise above the ventilatory anaerobic threshold (VAT) using 2 breaths of O2. The response to these transients was quantitated by the percentage change in ventilation, and exercise hyperventilation was quantitated by VE in excess of VCO2 predicted from the slope of delta VE/delta VCO2 below VAT in incremental exercise. Contrary to expectations, there was an inverse relation between the degree of exercise hyperventilation and the percentage reduction in exercise ventilation in response to O2. The significance of this observation and its integration with current thinking of the role of the peripheral chemoreceptor in mediating hyperventilation of heavy exercise is discussed.

Change in the peripheral CO2 chemoreflex from rest to exercise.

A single-breath CO2 test of peripheral chemosensitivity has recently been described, and elaborated based on model simulations. This study was designed to measure the peripheral CO2 chemoreflex at rest and during heavy exercise to see if carotid chemosensitivity to CO2 increased. Ten healthy, adult males performed an incremental exercise test to determine their ventilatory anaerobic threshold (VAT), and 20 minutes of steady-state exercise at a pre-determined power output above VAT. Arterialized venous blood was obtained during each minute of incremental exercise to verify development of metabolic acidosis. Carotid chemosensitivity was tested repeatedly at rest and in steady-state exercise by the ventilatory response to a single breath of 13% CO2 in air. The peripheral chemoreflex for CO2 for the group of subjects doubled from rest to exercise (mean 0.096 l.s-1.kPa-1) with all subjects showing an increase. We conclude that the gain of the carotid CO2 chemoreflex increases from rest to exercise at work above the VAT.

Blood lactate and pyruvate concentrations, and their ratio during exercise in healthy children: developmental perspective.

Blood concentrations of lactate normally increase during and after intense exercise as does the ratio of concentrations of lactate to pyruvate (L:P). Since there appear to be differences in blood lactate concentrations on exercise, in muscle metabolic enzyme activities, and in anaerobic capacity between children and adults, we speculated that there would be age related differences in lactate and pyruvate concentrations, and their ratio among children. Whole blood concentrations of lactate and pyruvate were measured in 28 healthy children aged 7-17 years, split into three age groups: less than 11, 11-14, and 15-17 years. Blood was drawn at rest, immediately after 6 min of exercise at one-third and two-thirds of maximum work capacity (Wmax), and 20 min after completion of work. Lactate and pyruvate concentrations increased significantly from rest to exercise at two-thirds Wmax [approximately 72% of peak oxygen consumption (VO2peak)]. Whereas greater increments in lactate concentration were seen with groups of increasing age, exercise-related increments in pyruvate concentrations were no different among age groups. There was a significant rise in L:P ratio on exercise, with greater increments found from the youngest to the oldest group. There were no sex differences. We concluded that in healthy children exercising at approximately 70% of VO2peak there is a rise in blood lactate concentration in excess of that of pyruvate, such that the L:P ratio rises to a degree determined by age. This suggests age dependent changes, perhaps coincident with puberty, in pathways involved in lactate production and/or elimination.

Effect of caffeine on the ventilatory response to inhaled carbon dioxide.

We investigated the effect of caffeine on the hypercapnic ventilatory response (HCVR) using steady state (SS) and rebreathing (RB) methods in 6 subjects. They received caffeine (5 mg/kg) or saline intravenously in a randomized, double-blind, crossover manner, with measurement of serum caffeine levels. PETCO2 and (VE), normalized for vital capacity (VC), were measured continually during RB and during the last 5 min of SS runs. The slope of the VE-PETCO2 response increased from 0.21 +/- 0.14 to 0.38 +/- 0.14 and from 0.23 +/- 0.12 to 0.59 +/- 0.45 VC.min-1.mmHg-1, measured by RB and SS respectively (P < 0.05). Plotting VT vs PETCO2 revealed a parallel shift (additive effect) in the response measured by RB after caffeine; but an increased slope (multiplicative effect) in the VT-PETCO2 relation measured in SS. We conclude that caffeine acts as a respiratory stimulant and increases the HCVR, but that assessment of the caffeine-CO2 interaction is dependent on the methodology employed.

Pulse oximetry in sickle cell disease.

Patients with sickle cell disease usually have mild hypoxaemia and their oxyhaemoglobin dissociation curve is shifted to the right. It follows that oxygen saturation in sickle cell disease should be lower than normal. Most subjects in this clinic had normal oxygen saturation by pulse oximetry, however. To improve the understanding of this paradox, arterialised capillary oxygen tension (PO2) and oxygen saturation were compared with simultaneously measured pulse oximeter saturation in 20 children with sickle cell disease. In addition, the PO2 at 50% haemoglobin saturation (P50) was compared with saturation measured by pulse oximetry in all 20 patients. It was found that saturation measured by pulse oximetry was, on the whole, similar to that calculated from the sampled blood. Individual deviations were not random, however, and were partly explained by differences in P50 values. It is concluded that pulse oximetry gives variable results in patients with sickle cell disease and should be used with caution to predict arterial saturation in this patient group.

Pulmonary function abnormalities in childhood sickle cell disease.

Pulmonary function tests in adults with sickle cell disease have shown a restrictive pattern that has been attributed to the sequelae of acute chest syndrome (ACS). We compared pulmonary function test results in 37 children with sickle cell anemia (20 with SS hemoglobin (HbSS), 14 with SC hemoglobin, and 3 with S beta hemoglobin) with those in 22 control subjects matched for sex, race, and height and compared pulmonary function in patients with and without a history of ACS. Of the 10 patients with a history of ACS, all but one had HbSS. Pulmonary function tests measured forced vital capacity (FVC), the diffusion capacity of carbon monoxide, and the plethysmographic determination of lung volumes. The FVC and forced expiratory volume in 1 second (FEV1), expressed as the percentage of the predicted value, were significantly less for those with HbSS with or without a history of ACS than for control subjects (p < 0.05), but the FEV1/FVC ratio, an index of airway obstruction, was normal in all groups. Total lung capacity was also significantly lower in patients with HbSS with or without a history of ACS than in control subjects (p < 0.05), but the ratio of residual volume to total lung capacity, another index of airway obstruction, was normal. We conclude that children with sickle cell disease, particularly those with HbSS, may have abnormally small lungs that function normally relative to their size; clustering of ACS episodes is not specifically associated with the observed abnormality.