Aminophylline reduces hypoxic ventilatory depression: possible role of adenosine

Newborn infants and animals typically exhibit a paradoxical ventilatory response to hypoxia. The depressive phase of the response has not been adequately explained. It has been suggested that hypoxia may cause the release of inhibitory neuromodulators which depress ventilation. We have postulated that the nucleoside, adenosine, may be involved because 1) it is rapidly released during hypoxia, 2) it depresses ventilation, and 3) theophylline, a competitive inhibitor, has successfully been used to treat apnea of prematurity. Herein we describe the effects of aminophylline on ventilation during hypoxia in the spontaneously breathing newborn piglet administered both rapidly after ventilatory depression has occurred (bolus) and before the onset of hypoxia (pretreatment). Ten percent oxygen breathing produced a typical biphasic ventilatory response. The decrease in minute ventilation was caused by a decrease in both tidal volume and respiratory frequency. The bolus administration of aminophylline reversed the depression in minute ventilation (p less than 0.001) by increasing tidal volume (p less than 0.002). Pretreatment with aminophylline decreased the amount of ventilatory depression (p less than 0.05) by preventing a decrease in respiratory frequency. We conclude that aminophylline, an adenosine antagonist, reduces the decrease in ventilation which occurs during hypoxia in the newborn. We speculate that adenosine may play a role in hypoxic ventilatory depression and respiratory control in the newborn.     

Impaired ventilatory responses to hypoxia in mice deficient in endothelin-converting-enzyme-1

Endothelin-converting-enzyme (ECE-1) catalyzes the proteolytic activation of big endothelin-1 to mature endothelin-1. Most homozygous ECE-1-/- embryos die in utero and show severe craniofacial, enteric, and cardiac malformations precluding ventilatory function assessment. In contrast, heterozygous ECE-1+/- embryos develop normally. Their respiratory function at birth has not been studied. Taking into account previous respiratory investigations in mice with endothelin-1 gene disruption, we hypothesized that ECE-1-deficient mice may have impaired ventilatory control. We analyzed ventilatory responses to hypercapnia (8% CO(2)) and hypoxia (10% O(2)) in newborn and adult mice heterozygous for ECE-1 deficiency (ECE-1+/-) and in their wild-type littermates (ECE-1+/+). Ventilation, breath duration, and tidal volume were measured using whole-body plethysmography. Ventilatory responses to hypoxia were significantly weaker in ECE-1+/- than in ECE-1+/+ newborn mice (percentage ventilation increase: 1 +/- 25% versus 33 +/- 29%, p = 0.010). Baseline breathing variables and ventilatory responses to hypercapnia were normal in the ECE-1+/- newborn mice. No differences were observed between adult ECE-1+/- and ECE-1+/+ mice. We conclude that ECE-1 is required for normal ventilatory response to hypoxia at birth.     

Effect of continuous positive airway pressure on the ventilatory response to CO2 in preterm infants

The effect of continuous positive airway pressure (CPAP) on the ventilatory response to CO2 in newborn infants is unknown. The CO2 response to 4% CO2 in air was studied in nine preterm infants without lung disease before and during administration of CPAP (4 to 5 cm H2O) delivered by face mask. Minute ventilation, tidal volume, respiratory frequency, and end-tidal PCO2 were measured, and the slope and intercept of the CO2 response were calculated. Respiratory pattern and changes in oxygenation were also analyzed by measuring inspiratory and expiratory time, mean inspiratory flow, mean expiratory flow, effective respiratory timing, end-tidal PO2, and transcutaneous PO2. CPAP significantly decreased minute ventilation from 278.7 to 197.6 mL/min/kg (P less than .001). Tidal volume and respiratory frequency were also significantly decreased. The slope of the CO2 response during CPAP was not significantly different from the slope before CPAP (36 v 33 mL/min/kg/mm Hg, P greater than .1), but the intercept was shifted to the right (P less than .001). The decrease in respiratory frequency was primarily due to a prolongation of expiratory time (P less than .05). In addition, transcutaneous PO2 increased during administration of CPAP (P less than .001). These findings indicate that: (1) CPAP significantly decreases ventilation in preterm infants without lung disease, affecting both tidal volume and respiratory frequency; (2) CPAP does not appreciably alter the ventilatory response to CO2; (3) the changes in respiratory frequency are primarily accounted for by a prolongation of expiratory time; (4) CPAP improves oxygenation.     

Respiratory responses to hypoxia/hypercapnia in small for gestational age infants influenced by maternal smoking

Aim: To determine any variation in the respiratory responses to hypoxia/hypercapnia of infants born small for gestational age (SGA) to smoking and to non-smoking mothers. METHODS: A total of 70 average for gestational age (AGA) infants (>36 weeks gestation, >2500 g, >25th centile for gestational age, and no maternal smoking), and 47 SGA infants (<10th centile for gestational age) were studied at 1 and 3 months of age, in quiet and active sleep. Respiratory test gases were delivered through a Perspex hood to simulate face down rebreathing by slowly allowing the inspired air to be altered to a CO(2) maximum of 5% and O(2) minimum of 13.5%. The change in ventilation with inspired CO(2) was measured over 5-6 minutes of the test. The slope of a linear curve fit relating inspired CO(2) to the logarithm of ventilation was taken as a quantitative measure of ventilatory asphyxial sensitivity (VAS). RESULTS: There was no significant difference in VAS between the AGA and SGA infants (0.25 v 0.24). However within the SGA group, VAS was significantly higher (p = 0.048) in the infants whose mothers smoked during pregnancy (0.26 (0.01); n = 24) than in those that did not (0.23 (0.01); n = 23). The change in minute ventilation was significantly higher in the smokers than the non-smokers group (141% v 119%; p = 0.03) as the result of a significantly larger change in respiratory rate (8 v 4 breaths/min; p = 0.047) but not tidal volume. CONCLUSIONS: Maternal smoking appears to be the key factor in enhancing infants' respiratory responses to hypoxia/hypercapnia, irrespective of gestational age.     

Postnatal nicotine exposure does not further compromise hypoxia defense mechanisms in prenatally nicotine-exposed lambs

AIMS: To determine whether combined pre- and postnatal nicotine exposure compared with prenatal exposure alone results in more compromised postnatal hypoxia defense mechanisms and further alteration of the postnatal breathing pattern (reduced tidal volume and increased respiratory rate). METHODS: Seven lambs exposed to nicotine prenatally (pN) (approximate maternal dose: 0.5 mg/kg/d) and seven lambs exposed to nicotine pre- and postnatally (ppN) (postnatal dose: 1.6-2 mg/kg/d) were studied without sedation at an average age of 5 d and 21 d during resting (room air) conditions, during exposure to 10% O2 and during a brief exposure to 100% O2. RESULTS: Resting minute ventilation, occlusion pressure, effective impedance, heart rate and mean arterial blood pressure were similar in the two groups during wakefulness and quiet sleep. Resting tidal volume was significantly higher in ppN than in pN lambs during wakefulness (9.4 +/- 0.7 vs 7.7 +/- 1.4 ml/kg, p < 0.05) and quiet sleep (9.8 +/- 0.6 vs 7.6 +/- 1.5 ml/kg, p < 0.01) at 5 d and also at 21 d during wakefulness (7.7 +/- 1.0 vs 6.2 +/- 1.1 ml/kg, p < 0.05). The ventilatory, heart rate and blood pressure responses to hypoxia were comparable in the two groups during both activity states. Time to arousal from quiet sleep in response to hypoxia was equivalent in the two groups. The ventilatory response to hyperoxia was not significantly different in the two groups during either activity state. CONCLUSION: Continued postnatal nicotine exposure after prenatal exposure did not further compromise hypoxia defense mechanisms after birth.     

Effects of theophylline on the pattern of spontaneous breathing in preterm infants less than 1000 g of birth weight

Proportional assist ventilation (PAV) amplifies the ventilatory effect of the spontaneous respiratory effort and therefore allows analysis of drug-induced changes in the spontaneous breathing pattern of subjects who depend on mechanical ventilatory assistance. We hypothesized that theophylline will reduce the number and duration of respiratory pauses and apneic events in infants less than 1000 g of birth weight on PAV. Twelve infants were studied: median birth weight was 773 g; gestational age 26.0 weeks and postnatal age 9 days. Measurements were obtained over a 2-h period before and after 5 mg/kg of intravenous theophylline. A respiratory pause was defined as cessation of breathing for at least the duration of three preceeding breaths. The total number of respiratory pauses and the number of apneas followed by either cardiac slowing (decrease in heart rate more than 10%) or bradycardia decreased significantly. Minute ventilation increased due to a rise in tidal volume from 5.6+/-1.3 to 6.1+/-1.2 ml/kg (p=0.004). The duration of respiratory pauses, the respiratory rate, and the number of apneas followed by desaturation did not change significantly. We conclude that theophylline stimulates spontaneous breathing in infants less than 1000 g, reduces the number of apneas, and increases minute volume by increasing the tidal volumes.     

Ventilatory responses to hypercapnia and hypoxia in conscious cystic fibrosis knockout mice Cftr-/-

This study was designed to examine the ventilatory performance and the lung histopathology of cystic fibrosis knockout mice (Cftr-/-) compared with heterozygous (Cftr+/-) or wild-type (Cftr+/+) littermates. Ventilation was recorded in conscious animals using whole-body plethysmography. Tidal volume (VT), respiratory frequency (f), and minute ventilation (VE) were measured during air breathing and in response to various levels of hypercapnia (2, 4, 6, or 8% CO2) or hypoxia (14, 12, 10, or 8% O2). The results for Cftr+/- and Cftr+/+ were pooled into one control group because they did not differ. In air and in response to hypercapnia, VE, VT, and f were similar in Cftr-/- mice and in controls. During graded hypoxia, VE was decreased in Cftr-/- mice at 10 and 8% O2 because of a lower f. Histology showed neither inflammation nor obstruction of airways in Cftr-/- mice. Morphometric analysis showed alveolar dilation as a result of either distension or impaired development. In conclusion, cystic fibrosis knockout mice have normal baseline breathing and ventilatory response to hypercapnia but a decreased ventilatory response to severe hypoxia. This latter result associated with the morphometric analysis suggests that Cftr-/- mice may exhibit immaturity of the respiratory system.     

Effect of external inspiratory loading on ventilation of premature infants

The ventilatory response of 11 growing premature infants to external inspiratory resistive loads was evaluated. Air flow, tidal volume, minute ventilation, inspiratory duration and total breath duration were measured before and after application of a flow resistive load. A significant (P less than 0.001) immediate decrease in minute ventilation and tidal volume was observed in all infants after load application. Minute ventilation and tidal volume remained decreased throughout the 10-min study period. Minute ventilation and tidal volume for the group decreased to 48 and 50% of control mean value, respectively. In addition, there was a significant (P less than 0.001) sustained increase in inspiratory time resulting in an increase in the ratio of inspiratory time/total respiratory time.     

Biphasic response of respiratory frequency to hypercapnea in preterm infants

The time course of the transient ventilatory response to a sudden change in inspired gas from room air to 4% CO2 in air was examined in 11 healthy preterm neonates. Changes in minute ventilation (VI), tidal volume (VT), and respiratory frequency (f) were determined over 4 to 5 min of CO2 inhalation during both quiet (QS) and active sleep (AS) in each infant. In both states there was a brisk increase of mean VI in response to 4% CO2, while mean VT increased more slowly and mean f only increased transiently at 1 to 2 min. Exponential curve fitting to the change in VI and VT for each infant accounted for 64 +/- 20% of the variance in VI during QS as compared to 30 +/- 18% during AS (p less than 0.003). In only six infants did exponential curves fitted to the changes in VI and VT during QS reach 90% of their steady state values within 4 to 5 min of CO2 exposure. Their time to reach 90% of steady state was always shorter for VI than VT (p less than 0.01). Frequency showed a biphasic response with a transient rise at 1 to 2 min (p less than 0.05) and return to control levels at steady state. These data indicate that not all preterm infants reach a new level of steady state ventilation within 4 to 5 min of 4% CO2 inhalation. Furthermore, many infants exhibit a biphasic response of f over time which causes VI to reach steady state prior to VT.     

The basomedial hypothalamus modulates the ventilatory response to hypoxia in neonatal rats

We sought to examine the role of the basomedial hypothalamus in the regulation of breathing in neonatal rats. Small basomedial hypothalamic lesions were produced by a lesioning agent, goldthioglucose, in 5-d-old male rat pups, and 2 d later, baseline ventilation and the ventilatory responses to hypoxia and hypercapnia were examined. When compared with vehicle-injected controls, goldthioglucose-lesioned rat pups had a significantly slower respiratory rate and longer expiratory time at baseline. Lesioned rats displayed an impaired increase in breathing frequency in response to hypoxia, and augmented increases in tidal volume and respiratory drive (the ratio of tidal volume to inspiratory time) during hypoxia relative to controls. Hypercapnic responses were not affected. These data demonstrate that cells in a restricted area of the hypothalamus specifically influence the respiratory response to hypoxia.     

Response to acute hypercapnia in the parents of victims of sudden infant death syndrome

The ventilatory response to acute hypercapnia was studied in 68 parents of victims of sudden infant death syndrome and 56 control subjects. Tidal volume, inspiratory time, and total respiratory cycle time were measured before and immediately after a vital capacity breath of 13% CO2 in oxygen. Instantaneous minute ventilation, mean inspiratory flow (tidal volume/inspiratory time), and respiratory timing (inspiratory time/total respiratory cycle time) were calculated. Both groups of subjects showed a marked increase in tidal volume (48.4% +/- 26.5%), instantaneous minute ventilation (56% +/- 35%), and tidal volume/inspiratory time (56.8% +/- 33.5%) after inhalation of the test gas, with little change in inspiratory time/total respiratory cycle time. There were no significant differences between the two groups for ventilation before or after inhalation of the test gas. The ventilatory response to acute hypercapnia is mediated by the peripheral chemoreceptors. These results suggest that an inherited abnormality of peripheral chemoreceptor function is unlikely to be a factor leading to sudden infant death syndrome.     

The effect of Escherichia coli endotoxin infusion on the ventilatory response to hypoxia in unanesthetized newborn piglets

To determine the effects of endotoxemia on the neonatal ventilatory response to hypoxia, 17 chronically instrumented and unanesthetized newborn piglets (相似文献   

Increased respiratory drive and limited adaptation to loaded breathing in bronchopulmonary dysplasia.

Ventilatory parameters and respiratory drive with and without an added acute resistive load were assessed in 11 healthy preterm infants and 11 infants with bronchopulmonary dysplasia (BPD). Lung mechanics (breathing frequency, tidal volume, minute ventilation, compliance, and resistance) were determined with esophageal manometry and pneumotachography. Respiratory drive was assessed by determining the airway pressure measured 100 ms after the onset of an inspiratory effort against an occlusion. Infants were studied at baseline and with an external inspiratory resistive load of 213.7 cm H2O/L/s. Infants with BPD had similar breathing frequency, tidal volume, and minute ventilation, lower compliance, and greater resistance and airway pressure at 100 ms than healthy preterm infants at rest. With loading, healthy preterm infants demonstrated increased airway pressure at 100 ms, whereas infants with BPD showed no change. Although the healthy preterm infants had decreased minute ventilation and tidal volume with loading, decreases in ventilation were greater in the infants with BPD. These data demonstrate that infants with BPD have responded to a chronic intrinsic load with increased drive. However, this may result in decreased ventilatory reserve and hence, a limited ability to adapt to acute pulmonary loads.     

Ventilatory responses to hypercapnia and hypoxia in Mash-1 heterozygous newborn and adult mice.

Normal control of breathing is characterized by maintenance of CO2 and O2 arterial pressures at constant levels by appropriate ventilatory responses to changes in CO2 production and O2 consumption. Abnormal development of this regulatory system during embryogenesis may produce early impairments in chemosensitivity, as in congenital central hypoventilation syndrome. The present study addresses the role of the mammalian achaetescute homologous gene (Mash-1) in the development of respiratory control. We analyzed ventilatory responses to hypercapnia (8% CO2, 21% O2, 71% N2) and hypoxia (10% O2, 3% CO2, 87% N2) in newborn and adult Mash-1 heterozygous mice (Mash-1+/-) and their wild-type littermates (Mash-1+/+). Ventilation, breath duration, and tidal volume were measured using whole-body plethysmography. Ventilatory responses to hypercapnia were significantly weaker in newborn male Mash-1+/- compared with Mash-1+/+ mice as a result of a weaker breath-duration response. No differences were observed between adult Mash-1+/- and Mash-1+/+ mice. Our data suggest that Mash-1 may be involved in respiratory control development via mechanisms linked to the X chromosome.     

Predictors of successful extubation of preterm low-birth-weight infants with respiratory distress syndrome.

OBJECTIVE: The aim of the study was to measure pulmonary mechanics in infants with respiratory distress syndrome before extubation and to correlate pulmonary function values with successful extubation. DESIGN: Clinical study. SETTING: Neonatal intensive care unit. PATIENTS: Fifty-one infants (birth weight, 1158.6 +/- 150.6 g; gestational age, 29.1 +/- 2.0 wks). INTERVENTIONS: Ventilation and daily ventilatory management. MEASUREMENTS AND MAIN RESULTS: Of the 51 infants studied, 35 (60.8%) were successfully extubated, whereas 16 (39.2%) required reintubation and mechanical ventilation within 72 hrs after extubation. All patients met the clinical and biochemical criteria for extubation. Variables of artificial ventilation before extubation were minimal in all the studied cases (Fio(2) 6 mL/kg, minute ventilation of >309 mL/kg/min, work of breathing of <0.172 J/L, dynamic compliance of >/=1 mL/cm H(2)O/kg, and resistance of airways of 相似文献   

Comparing the effects of nasal synchronized intermittent positive pressure ventilation (nSIPPV) and nasal continuous positive airway pressure (nCPAP) after extubation in very low birth weight infants

In this study we hypothesized that nasal synchronized intermittent positive pressure ventilation (nSIPPV) would provide more ventilatory support than nasal continuous positive airway pressure (nCPAP) in the immediate post-extubation period in very low birth weight (VLBW) infants. We tested this hypothesis by comparing the effects of these two ventilatory techniques on ventilation, gas exchange, and patient inspiratory effort in 11 preterm infants immediately after extubation. All neonates studied (BW: 1141+/-(SEM) 53 g; GA: 28.1+/-(SEM) 0.5 wks) had received mechanical ventilation because of respiratory distress at birth and were extubated by day 14 of life. Nasal SIPPV and nCPAP were applied in random order to each infant after extubation so that each was his/her own control. Both nCPAP and nSIPPV were delivered at end-expiratory pressures (PEEP) of 3 cm H2O. Inspiratory times (Ti) and peak inspiratory pressures set during nSIPPV were the same as those used at the time of extubation. Recordings lasted 45 min in each mode of ventilation. Tidal volume (Vt), minute volume (Ve), respiratory rate (RR), airway pressure (Paw), transcutaneous PO2 (TcPO2) and PCO2 (TcPCO2) as well as phasic esophageal pressure deflections (Pe), as an estimate of inspiratory effort, were measured. The measurements obtained during both modes of ventilation indicated significant differences between the two techniques. Indeed, application of nSIPPV was associated with a statistically significant increase in Vt and Ve. In addition, Pe decreased by 30% during nSIPPV (P<0.01). TcPCO2 was statistically significantly lower during nSIPPV than nCPAP, and RR as well. These data therefore suggest that nSIPPV may provide more ventilatory support than nCPAP in the post-extubation period with less patient inspiratory effort.     

仰俯卧位对新生儿肺炎患儿肺功能的影响(英文)

目的　探讨仰、俯卧位对足月新生儿肺炎患儿肺功能的影响 ,寻求足月新生儿肺炎患儿的合理体位。方法　应用美国BicoreCP 10 0新生儿肺功能仪分别检测 30例新生儿肺炎患儿仰、俯卧位时的呼吸频率、潮气量、每分通气量、气道阻力、动态肺顺应性和呼吸功。结果　俯卧位呼吸频率和气道阻力明显低于仰卧位 [(4 4 .3±9.2bpm min)vs (4 8.0± 10 .6bpm min) ;(15 3.1± 5 0 .4 )cmH2 O (L .sec)vs (2 11.9± 6 3.1)cmH2 O (L .sec) ,差异有极显著性意义 ,P <0 .0 1];俯卧位潮气量、每分通气量、动态肺顺应性和呼吸功明显高于仰卧位 [(2 .2 9±0 .4 6ml kg)vs (1.6 5± 0 .5 0ml kg) ;(0 .0 95± 0 .0 2 4 )L (min .kg)vs (0 .0 75± 0 .0 2 2 )L (min .kg) ;(0 .6 2 1±0 .2 14 )ml (cmH2 O .kg)vs (0 .389± 0 .115 )ml (cmH2 O .kg) ;(8.9± 3.5 )gm (cm .kg)vs (5 .9± 2 .7)gm (cm .kg) ,差异有极显著性意义 ,P <0 .0 1]。结论　俯卧位可改善新生儿肺炎患儿潮气量、每分通气量和动态肺顺应性 ,降低呼吸频率和气道阻力 ,提示俯卧位是改善新生儿肺炎患儿肺功能的适宜体位。     

Dynamics of breathing during partial liquid ventilation in spontaneously breathing rabbits supported by elastic and resistive unloading

Partial liquid ventilation (PLV) has been shown to improve gas exchange in paralyzed animals and in humans with lung disease. This study tests the hypothesis that PLV combined with respiratory mechanical unloading results in stable ventilation and gas exchange in spontaneously breathing animals. Ten adult anesthetized, intubated, and spontaneously breathing rabbits received ventilatory support by respiratory mechanical unloading (Fi(O2) 1.0). Minute ventilation, respiratory rate, esophageal pressure, heart rate, and arterial blood pressure were recorded continuously during gas ventilation for 1 h. Next, 30 mL/kg of perfluorocarbon was instilled into the endotracheal tube. Thereafter, data were recorded again for 1 h (PLV). Arterial blood gases were obtained at the end of each period. Variability of recorded data was assessed by calculating coefficients of variation using data obtained each minute. Compared with gas ventilation, minute ventilation was larger during PLV (275 +/- 93 versus 368 +/- 89 mL/kg/min.; p < 0.01). This was because of a higher respiratory rate during PLV (58 +/- 23 versus 74 +/- 18 breaths/min; p < 0.05), while tidal volume was similar. Compared with gas ventilation, Pa(O2) was lower during PLV (61.31 +/- 5.32 versus 47.35 +/- 8.38 kPa; p < 0.05). Pa(CO2), peak esophageal pressure deflections, heart rate, mean arterial blood pressure, and coefficients of variation for minute ventilation, tidal volume, respiratory rate, and peak esophageal pressure were not significantly different between modes. Compliance was decreased and resistance and work of breathing were increased during PLV. We conclude that stable ventilation and gas exchange may be achieved during PLV combined with mechanical unloading in spontaneously breathing animals without lung disease.     

Ventilatory control and carbon dioxide response in preterm infants with idiopathic apnea

Idiopathic apnea in preterm infants, more than 30 weeks of gestation, after the first week of life is uncommon and poorly understood. To study ventilatory control in these infants we measured minute ventilation, respiratory frequency, tidal volume, end-tidal oxygen pressure and carbon dioxide pressure, and transcutaneous oxygen pressure before and during the fifth minute of breathing 4% carbon dioxide in air. Nine healthy preterm infants and eight infants with three or more episodes of apnea (greater than or equal to 20 s) in 24 hours were studied during active sleep. We found that infants with apnea had a significantly increased alveolar carbon dioxide pressure while respiratory frequency, minute ventilation, and slope were significantly decreased. Alveolar-transcutaneous oxygen gradients were essentially unchanged. These preterm infants with apnea have a decreased carbon dioxide sensitivity. They have a decreased minute ventilation primarily as a result of decreased respiratory frequency and their alveolar-transcutaneous oxygen gradient is normal. Our findings suggest that the major deficit in these infants is a central disturbance in the regulation of breathing.     

A method of assessing ventilatory responses to chemoreceptor stimulation in infants

Various methods of assessing infant chemoreceptor responses have been reported in the literature. However, equipment dead space, trigeminal stimulation and inherent respiratory variability may have affected the results. A method is presented which attempts to reduce the effect of these factors and thereby isolate the chemoreceptor response. Inspiratory gas was delivered into a lightweight face mask with a pliable rim, minimal dead space and a connected pneumotachograph. Ventilatory data were computed breath by breath. Computer-controlled electromagnetic valves allowed instantaneous switching between air and different gas mixtures, repeated in a randomized sequence. In 18 healthy term neonates, the mask increased ventilation by 12% (95% confidence interval 6-18%), measured by calibrated strain-gauge bands. The effect on respiratory frequency and tidal volume differed significantly between sleep states. Neonates were challenged with short-lasting hyperoxia, mild hypoxia, rebreathing and mild hypercapnia. Coherent averaging of several ventilatory responses from each sleep state reduced the variability while maintaining a high time-resolution.