Development of stability of the respiratory system in preterm infants

Chest wall distortion leads to increased minute volume displacement of the diaphragm (MVDD) and diaphragmatic work (DW) in preterm infants. Lung mechanics, MVDD, and DW were measured at weekly intervals in six preterm infants between 29 and 36 wk postconceptional age. Over the period of study, MVDD and DW decreased significantly, whereas dynamic lung compliance consistently increased. There was no consistent change in the pulmonary ventilation, total pulmonary resistance, the work performed on the lungs, or the change in intraesophageal pressure with tidal breathing. The improvement in the stability of the chest wall, as indicated by the change in these dynamic measurements of diaphragmatic function, parallels the decrease in static chest wall compliance and the clinical course of the resolution of apnea of prematurity.     

Lung mechanics and neuromuscular output during CO2 inhalation after airway anesthesia

Airway anesthesia with aerosolized lidocaine has been associated with an increase in minute ventilation (VE) during CO2 inhalation. The increase in VE may be due to increased neuromuscular output or decreased mechanical load on breathing. To evaluate this we measured VE, breathing pattern, mouth occlusion pressure, and lung mechanics in 20 normal subjects during room-air breathing and then inhalation of 6% CO2-94% O2, before and after airway anesthesia. Measurements of lung mechanics included whole-lung resistance, dynamic and static compliance, and functional residual capacity. Airway anesthesia had no detectable effect on any measurements during room-air breathing. During CO2 inhalation, airway anesthesia produced increases in VE and mean inspiratory flow rate (VT/TI) and more negative inspiratory pleural pressure but had no detectable effect on lung mechanics or mouth occlusion pressure. Pleural pressure was more negative during the latter 25% of inspiration. We concluded that airway receptors accessible to airway anesthesia play a role in determining neuromuscular output during CO2 inhalation.     

The effect of body temperature on the dynamic respiratory system compliance–breathing frequency relationship in the rat

The mechanical inhomogeneity of the respiratory system is frequently investigated by measuring the frequency dependence of dynamic compliance, but no data are currently available describing the effects of body temperature variations. The aim of the present report was to study those effects in vivo. Peak airway pressure was measured during positive pressure ventilation in eight anesthetized rats while breathing frequency (but not tidal volume) was altered. Dynamic compliance was calculated as the tidal volume/peak airway pressure, and measurements were taken in basal conditions (mean rectal temperature 37.3 °C) as well as after total body warming (mean rectal temperature 39.7 °C). Due to parenchymal mechanical inhomogeneity and stress relaxation-linked effects, the normal rat respiratory system exhibited frequency dependence of dynamic lung compliance. Even moderate body temperature increments significantly reduced the decrements in dynamic compliance linked to breathing rate increments. The results were analyzed using Student’s and Wilcoxon’s tests, which yielded the same results (p < 0.05). Body temperature variations are known to influence respiratory mechanics. The frequency dependence of dynamic compliance was found, in the experiments described, to be temperature-dependent as temperature variations affected parenchymal mechanical inhomogeneity and stress relaxation. These results suggest that body temperature variations should be taken into consideration when the dynamic compliance–breathing frequency relationship is being examined during clinical assessment of inhomogeneity of lung parenchyma in patients.     

Oral administration of diltiazem decreases ventilation and metabolism of Syrian hamsters

1. Diltiazem at doses of 2.5, 25, and 50 mg/kg caused a reduction of minute ventilation of hamsters over a 60 min period compared to saline administration. 2. The decrease of ventilation was due to a fall in frequency of breathing, but predominantly due to a decrease of tidal volume. 3. The pattern of metabolic response of hamsters to diltiazem was different to the ventilatory response--but metabolic rate was decreased in all animals receiving diltiazem by 60 min compared to pregavage values.     

Anesthesia alters the pattern of aerosol retention in hamsters

General anesthesia was used to produce nonventilated areas of the lung, and aerosol inhalation was used to locate these areas, assuming that no aerosol deposits in a nonventilated region. Male Syrian golden hamsters were anesthetized with pentobarbital sodium (90 mg/kg), which reduced respiratory frequency, tidal volume, minute volume, and O2 consumption to 61, 41, 24, and 36%, respectively, of the corresponding awake levels. Awake and anesthetized hamsters were exposed to the aerosol for 30 min; then the lungs were excised, dried at total lung capacity, sliced into sections, and dissected into pieces. Autoradiographs were made of slices, and the activity and weight of pieces were determined. The evenness index (EI), a measure of the uniformity of retention, was calculated for each piece. With complete uniformity of retention, all EI's would be 1.0. In awake animals, only 0.2% (by wt) of the lungs had little or no retention (EI's less than 0.20). More particles deposited in the apex than in the base of the lungs. General anesthesia for extended periods of time with no deep breaths alters ventilation and therefore the distribution of aerosol retention. Many regions of the lungs in the anesthetized animals received few or no particles (11.6% of lungs had EI less than 0.20); however, no consistent pattern was observed in the location of these areas from animal to animal. The apex-to-base gradient for retention in these animals was also reversed. Radioactive aerosols can be used as probes to indicate the extent and distribution of nonventilated areas in the lungs.     

Effects of vagotomy on respiratory mechanics in newborn and adult pigs

We have examined breathing patterns and respiratory mechanics in anesthetized tracheostomized newborn piglets and adult pigs and the changes determined by cervical bilateral vagotomy. Piglets had a respiratory system compliance and resistance, on a per kilogram basis, respectively, higher and smaller than the adults. After vagotomy neither variable changed in the newborn, but resistance dropped in the adult. This may suggest that efferent vagal control of bronchomotor tone is more pronounced in the adult. Respiratory system time constant was longer in newborns both before and after vagotomy. The distortion of the chest wall, examined as the ratio between the volume inhaled spontaneously and the passive volume for the same abdominal motion, was more marked in newborns, reflecting their higher chest wall compliance. The work per minute, computed from the pressure and volume changes, was larger in piglets. After vagotomy the external work per minute was not different; however, the larger tidal volumes were accompanied by a larger chest distortion. This may indicate that vagal control of the breathing pattern, by limiting the depth of inspiration and hence the amount of chest distortion, has implications on the energetics of breathing.     

Proteoglycan fragmentation and respiratory mechanics in mechanically ventilated healthy rats.

This research investigated whether stretching of lung tissue due to increased positive alveolar pressure swings during mechanical ventilation (MV) at various tidal volumes (V(T)) might affect the composition and/or structure of the glycosaminoglycan (GAG) components of pulmonary extracellular proteoglycans. Experiments were performed in 30 healthy rats: 1) anesthetized and immediately killed (controls, C-0); 2) anesthetized and spontaneously breathing for 4 h (C-4h); and 3) anesthetized, paralyzed, and mechanically ventilated for 4 h with air at 0-cmH(2)O end-expiratory pressure and V(T) of 8 ml/kg (MV-1), 16 ml/kg (MV-2), 24 ml/kg (MV-3), or 32 ml/kg (MV-4), adjusting respiratory rates at a minute ventilation of 270 ml/min. Compared with C-0 and C-4h, a significant reduction of dynamic and static compliance of the respiratory system and of the lung was observed only in MV-4, while extravascular lung water significantly increased in MV-3 and MV-4, but not in MV-1 and MV-2. However, even in MV-1, MV induced a significant fragmentation of pulmonary GAGs. Extraction of covalently bound GAGs and wash out of loosely bound or fragmented GAGs progressively increased with increasing V(T) and was associated with increased expression of local (matrix metalloproteinase-2) and systemic (matrix metalloproteinase-9) activated metalloproteases. We conclude that 1) MV, even at "physiological" low V(T), severely affects the pulmonary extracellular architecture, exposing the lung parenchyma to development of ventilator-induced lung injury; and 2) respiratory mechanics is not a reliable clinical tool for early detection of lung injury.     

Influence of tidal volume on respiratory compliance in anesthetized infants and young children

Recent studies have suggested a close association between total respiratory compliance (Crs) and tidal volume in anesthetized paralyzed infants who are being artificially ventilated. To investigate this further, the multiple occlusion technique was used to measure Crs in 20 anesthetized infants and young children (aged 1-25 mo) before elective surgery. Measurements were made after intubation 1) during spontaneous breathing (SB), 2) after administration of a non-depolarizing muscle relaxant with tidal volume and frequency mimicking that during SB, and 3) with the child still paralyzed but tidal volume approximately double that during SB. Compared with values obtained during SB, there was no significant change in Crs after paralysis when ventilation matched the child's own pattern (P greater than 0.2). When ventilated with the larger tidal volumes, the infants showed a highly significant increase in Crs (mean 62%, range 14-158%, P less than 0.0001). These results may have implications not only for studies performed during anesthesia but also when infants were monitored in the intensive care setting. Values of Crs obtained in ventilated infants may reflect both the mechanical behavior of the respiratory system and the pattern of ventilation at the time of measurement.     

Identification of respiratory vagal feedback in awake normal subjects using pseudorandom unloading.

Evidence of the Hering-Breuer reflex has been found in humans during anesthesia and sleep but not during wakefulness. Cortical influences, present during wakefulness, may mask the effects of this reflex in awake humans. We hypothesized that, if lung volume were increased in awake subjects unaware of the stimulus, vagal feedback would modulate breathing on a breath-to-breath basis. To test this hypothesis, we employed proportional assist ventilation in a pseudorandom sequence to unload the respiratory system above and below the perceptual threshold in 17 normal subjects. Tidal volume, integrated respiratory muscle pressure per breath, and inspiratory time were recorded. Both sub- and suprathreshold stimulation evoked a significant increase in tidal volume and inspiratory flow rate, but a significant decrease in inspiratory time was present only during the application of a subthreshold stimulus. We conclude that vagal feedback modulates respiratory timing on a breath-by-breath basis in awake humans, as long as there is no awareness of the stimulus.     

Stable small animal ventilation for dynamic lung imaging to support computational fluid dynamics models

Pulmonary computational fluid dynamics models require that three-dimensional images be acquired over multiple points in the dynamic breathing cycle without breath holds or changes in ventilatory mechanics. With small animals, these requirements can result in long imaging times (～90 minutes), over which lung mechanics, such as compliance, may gradually change if not carefully monitored and controlled. These changes, caused by derecruitment of parenchymal tissue, are manifested as an upward drift in peak inspiratory pressure (PIP) or by changes in the pressure waveform and/or lung volume over the course of the experiment. We demonstrate highly repeatable mechanical ventilation in anesthetized rats over a long duration for dynamic lung x-ray computed tomography (CT) imaging. We describe significant updates to a basic commercial ventilator that was acquired for these experiments. Key to achieving consistent results was the implementation of periodic deep breaths, or sighs, of extended duration to maintain lung recruitment. In addition, continuous monitoring of breath-to-breath pressure and volume waveforms and long-term trends in PIP and flow provide diagnostics of changes in breathing mechanics.     

Effects of increased ventilation on lung lymph flow in unanesthetized sheep

To determine the effect of an increase in spontaneous minute ventilation on lung fluid balance, we added external dead space to the breathing circuit of six tracheostomized, unanesthetized, spontaneously breathing sheep in which lung lymph fistulas had been created surgically. The addition of 120-180 ml of dead space caused minute ventilation to increase by 50-100% (secondary to increases in both tidal volume and frequency), without changing pulmonary arterial pressure, pulmonary capillary wedge pressure, cardiac output, or arterial blood gas tensions. The increase in spontaneous ventilation was associated with an average increase of 27% in lung lymph flow (P less than 0.05) and an average reduction of 11% in the lymph-to-plasma concentration ratio (L/P) for total protein (P less than 0.05). Lymph flow and L/P for total protein approached stable values after 2-3 h of hyperpnea, and the increase in lymph flow persisted for at least 18 h of dead-space breathing. Removal of dead space was associated with a rapid return (within 45 min) of lymph flow to base-line levels. These results suggest that hyperpnea increases the pulmonary transvascular filtration rate. Since no changes in vascular pressures or cardiac output were observed, this increase in transvascular filtration is most likely due to a fall in interstitial fluid pressure.     

Ventilatory response to sustained hypoxia in carotid body denervated rats

Hypoxia stimulates ventilation, but when it is sustained, a decline in the ventilatory response is seen. The mechanism responsible for this decline lies within the CNS, but still remains unknown. In this study, we attempted to elucidate the possible role of hypoxia-induced depression of respiratory neurons by comparing the ventilatory response to hypoxia in intact rats and those with denervated carotid bodies. A whole-body plethysmograph was used to measure tidal volume, frequency of breathing and minute ventilation (VE) in awake and anesthetized intact rats and rats after carotid body denervation during exposure to hypoxia (FIO2 0.1). Fifteen-minute hypoxia induced an initial increase of VE in intact rats (to 248% of control ventilation in awake and to 227% in anesthetized rats) followed by a consistent decline (to 207% and 196% of control VE, respectively). Rats with denervated carotid bodies responded with a smaller increase in VE (to 134% in awake and 114% in anesthetized animals), but without a secondary decline (145% and 129% of control VE in the 15th min of hypoxia). These results suggest that afferentation from the carotid bodies and/or the substantial increase in ventilation are crucial for the biphasicity of the ventilatory response to sustained hypoxia and that a central hypoxic depression cannot fully explain the secondary decline in VE.     

Influence of halothane on control of breathing in intact and decerebrated cats

The effects of halothane anesthesia have been investigated in intact and in decerebrated cats. Pulmonary ventilation and breathing pattern were studied during room-air breathing, hypercapnia, and O2 inhalation. The following results have been demonstrated. First, halothane anesthesia does not modify pulmonary ventilation, but a tachypnea much more intense in intact than in decerebrated cats is observed. This indicates that halothane-induced tachypnea originates mainly in structures rostral to the brain stem. Second, decerebrated animals exhibit a breathing pattern and a ventilatory response to CO2 similar to those of intact conscious cats, suggesting that forebrain facilitatory and inhibitory influences on brain stem are cancelled out by decerebration. However, the tidal volume vs. inspiratory duration relationship observed in decerebrated cats differs from that in conscious cats. Finally, during halothane anesthesia, ventilatory response to CO2 is markedly depressed. Third, during O2 inhalation, except in decerebrated, anesthetized animals, ventilation is only slightly depressed. This suggests that central stimulatory effect of O2 is enhanced and/or that peripheral chemoreceptor drive is reduced.     

Influence of lung volume and left atrial pressure on reverse pulmonary venous blood flow

Infarction of the lung is uncommon even when both the pulmonary and the bronchial blood supplies are interrupted. We studied the possibility that a tidal reverse pulmonary venous flow is driven by the alternating distension and compression of alveolar and extra-alveolar vessels with the lung volume changes of breathing and also that a pulsatile reverse flow is caused by left atrial pressure transients. We infused SF6, a relatively insoluble inert gas, into the left atrium of anesthetized goats in which we had interrupted the left pulmonary artery and the bronchial circulation. SF6 was measured in the left lung exhalate as a reflection of the reverse pulmonary venous flow. No SF6 was exhaled when the pulmonary veins were occluded. SF6 was exhaled in increasing amounts as left atrial pressure, tidal volume, and ventilatory rates rose during mechanical ventilation. SF6 was not excreted when we increased left atrial pressure transients by causing mitral insufficiency in the absence of lung volume changes (continuous flow ventilation). Markers injected into the left atrial blood reached the alveolar capillaries. We conclude that reverse pulmonary venous flow is driven by tidal ventilation but not by left atrial pressure transients. It reaches the alveoli and could nourish the alveolar tissues when there is no inflow of arterial blood.     

Effect of anaesthesia on the pattern of breathing.

The pattern of breathing of male rats was studied after stimulating respiration with carbon dioxide at different levels of general anaesthesia. Anaesthesia was induced by the inhalation of halothane or by the i.p. injection of urethane. Ventilation values were measured in intubated rats in body plethysmograph. It was found that a linear relationship between minute ventilation and tidal volume was maintained during the decrease of minute ventilation due to deepening of anaesthesia. The slope of the relationship after stimulating respiration with carbon dioxide also diminished during deeper anaesthesia. The duration of inspiration did not alter significantly, despite marked changes in tidal volume. Tidal volume correlated with the duration of expiration at different anaesthesia levels. In vagotomized rats, the duration of expiration shortened as ventilation was depressed by deepening anaesthesia.     

Role of the carotid bodies in chemosensory ventilatory responses in the anesthetized mouse.

We examined the effects of carotid body denervation on ventilatory responses to normoxia (21% O2 in N2 for 240 s), hypoxic hypoxia (10 and 15% O2 in N2 for 90 and 120 s, respectively), and hyperoxic hypercapnia (5% CO2 in O2 for 240 s) in the spontaneously breathing urethane-anesthetized mouse. Respiratory measurements were made with a whole body, single-chamber plethysmograph before and after cutting both carotid sinus nerves. Baseline measurements in air showed that carotid body denervation was accompanied by lower minute ventilation with a reduction in respiratory frequency. On the basis of measurements with an open-circuit system, no significant differences in O2 consumption or CO2 production before and after chemodenervation were found. During both levels of hypoxia, animals with intact sinus nerves had increased respiratory frequency, tidal volume, and minute ventilation; however, after chemodenervation, animals experienced a drop in respiratory frequency and ventilatory depression. Tidal volume responses during 15% hypoxia were similar before and after carotid body denervation; during 10% hypoxia in chemodenervated animals, there was a sudden increase in tidal volume with an increase in the rate of inspiration, suggesting that gasping occurred. During hyperoxic hypercapnia, ventilatory responses were lower with a smaller tidal volume after chemodenervation than before. We conclude that the carotid bodies are essential for maintaining ventilation during eupnea, hypoxia, and hypercapnia in the anesthetized mouse.     

Positive outcome of average volume-assured pressure support mode of a Respironics V60 Ventilator in acute exacerbation of chronic obstructive pulmonary disease: a case report

ABSTRACT: INTRODUCTION: We were able to treat a patient with acute exacerbation of chronic obstructive pulmonary disease who also suffered from sleep-disordered breathing by using the average volume-assured pressure support mode of a Respironics V60 Ventilator (Philips Respironics: United States). This allows a target tidal volume to be set based on automatic changes in inspiratory positive airway pressure. This removed the need to change the noninvasive positive pressure ventilation settings during the day and during sleep. The Respironics V60 Ventilator, in the average volume-assured pressure support mode, was attached to our patient and improved and stabilized his sleep-related hypoventilation by automatically adjusting force to within an acceptable range. CASE PRESENTATION: Our patient was a 74-year-old Japanese man who was hospitalized for treatment due to worsening of dyspnea and hypoxemia. He was diagnosed with acute exacerbation of chronic obstructive pulmonary disease and full-time biphasic positive airway pressure support ventilation was initiated. Our patient was temporarily provided with portable noninvasive positive pressure ventilation at night-time following an improvement in his condition, but his chronic obstructive pulmonary disease again worsened due to the recurrence of a respiratory infection. During the initial exacerbation, his tidal volume was significantly lower during sleep (378.9 +/- 72.9mL) than while awake (446.5 +/- 63.3mL). A ventilator that allows ventilation to be maintained by automatically adjusting the inspiratory force to within an acceptable range was attached in average volume-assured pressure support mode, improving his sleep-related hypoventilation, which is often associated with the use of the Respironics V60 Ventilator. Polysomnography performed while our patient was on noninvasive positive pressure ventilation revealed obstructive sleep apnea syndrome (apnea-hypopnea index = 14), suggesting that his chronic obstructive pulmonary disease was complicated by obstructive sleep apnea syndrome. CONCLUSION: In cases such as this, in which patients with severe acute respiratory failure requiring full-time noninvasive positive pressure ventilation therapy also show sleep-disordered breathing, different ventilator settings must be used for waking and sleeping. On such occasions, the Respironics V60 Ventilator, which is equipped with an average volume-assured pressure support mode, may be useful in improving gas exchange and may achieve good patient compliance, because that mode allows ventilation to be maintained by automatically adjusting the inspiratory force to within an acceptable range whenever ventilation falls below target levels.     

Breathing patterns in anesthetized cats and the concept of minimum respiratory effort

Theoretical studies dealing with the principle of minimal respiratory effort usually make use of sinusoidal or saw-tooth-like breathing patterns. Recent observations in anesthetized cats have shown that the driving pressure waveform for inspiration can be described by a power function of time and that most of expiration is passive. This driving pressure waveform, however, results in breathing patterns that differ from those described above. For this reason, we have reevaluated in anesthetized cats the principle of minimal respiratory effort by computing optimal duration of inspiration (TI) and optimal tidal volume (VT) for different ventilatory conditions using actual driving pressure waveforms. The results are in qualitative agreement with the experimental observations; i.e., optimal TI decreases and optimal VT increases with increasing minute ventilation. On the average, a good agreement is found between measured and computed values of TI. In some cats, however, there are substantial differences between observed and predicted values of TI, which can probably be ascribed to inaccuracies in the data used in our computations. Despite its limitations, the present model analysis is more realistic than previous ones because actual driving pressure waveforms are used together with actual values of effective inspiratory impedance.     

Endothelin involvement in respiratory centre activity.

To evaluate the role of endothelin (ET) in respiratory homeostasis we studied the effects of the ET(A) and ET(B) receptor blocking agent bosentan on respiratory mechanics and control in seven anaesthetised spontaneously breathing pigs, for 180 min after single bolus administration (20 mg/kg i.v.). The results show that the block of ET receptors induced a significant increase in compliance and decrease in resistance of the respiratory system, entailing a significant reduction of diaphragmatic electromyographic activity, without affecting the centroid frequency of the power spectrum. Bosentan administration induced a significant increase in tidal volume (V(T)), accompanied by a significant decrease in respiratory frequency, without any significant change in pulmonary ventilation, CO(2) arterial blood gas pressure or pH. Since the relationship between V(T) and inspiratory time remained substantially constant after bosentan administration, the changes in respiratory pattern appear to be the result of an upward shift in inspiratory off-switch threshold. Both inspiratory and expiratory times during occluded breathing were increased by block of ET receptors, suggesting also a central respiratory neuromodulator effect of ET. In conclusion the present results suggest that the block of ET receptors in spontaneously breathing pigs exerts a role on mechanical properties of the respiratory system as well as on peripheral and central mechanisms of breathing control.