Neurochemicals in the infant lung.
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Bombesin↗
Biomedical subjects
C E Sullivan
Publications and source records attributed to C E Sullivan.
Non-invasive technique for examining the respiratory proprioceptor system in man.
Our technique enables non-invasive experiments to be conducted on the proprioceptor part of respiratory control, while eliminating misleading responses due to interaction with the chemoreceptor system; interaction was prevented by stabilizing arterial PO2 and PCO2 with the aid of an optimal regulator based on a mini-computer which controlled the inspired gas mixture. The proprioceptor system in a human was disturbed by applying positive pressure pulses at the mouth, responses were derived from continuous air-flow measurement. The classical inflation inhibiting reflex and an effect akin to Head's paradoxical reflex were demonstrated.
Biomedical Engineering↗
Mutagenicity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in the granuloma pouch assay.
The rat granuloma pouch assay was used to assess the in vivo mutagenic potential of 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ), a heterocyclic aromatic amine which is formed during the frying of meat and broiling of fish. The assay was performed with and without pre-induction by Aroclor. In the initial experiment IQ was injected directly into the pouch of non-induced rats. A 10-fold increase in mutation frequencies was obtained with the 2.0 mg/pouch dose of IQ with uninduced cell populations. In a second study IQ was injected intraperitoneally and into the pouch of rats that had been pre-induced with Aroclor. The dose of IQ administered varied from 0.1 to 2.0 mg/pouch. A 10-fold increase in mutation frequencies was obtained with the 2.0 mg/pouch dose of IQ with uninduced cell populations. Aroclor treatment produced no significant increase in mutation frequencies over uninduced animals. Its mutagenic effect is about 10-fold weaker than that of benzo[a]pyrene or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG).
Animals↗
Arousal responses to airway occlusion in sleeping dogs: comparison of nasal and tracheal occlusions.
Previous studies have shown that the arousal threshold to hypoxia, hypercapnia, and tracheal occlusions is greatly depressed in rapid-eye-movement (REM) sleep compared with slow-wave sleep (SWS). The aim of this study was to compare the arousal thresholds in SWS and REM sleep in response to an upper airway pressure stimulus. We compared the waking responses to tracheal (T) vs. nasal (N) occlusion in four unanesthetized, naturally sleeping dogs. The dogs either breathed through a tracheal fistula or through the snout using a fiberglass mask. A total of 295 T and 160 N occlusion tests were performed in SWS and REM sleep. The mean time to arousal during N and T tests was variable in the same dog and among the dogs. The mean time to arousal in SWS-tracheal occlusion was longer than that in N tests in only two of the four dogs. The total number of tests inducing arousal within the first 15 s of SWS-nasal occlusion tests was significantly more than that of T tests (N: 47%; T: 27%). There was a marked depression of arousal within the initial 15 s of REM sleep in T tests compared with N tests (N: 21%; T: 0%). The frequency of early arousals in REM tests was less than that of SWS for both N and T tests. The early arousal in N occlusion is in sharp contrast to the well-described depressed arousal responses to hypoxia, hypercapnia, and asphyxia. This pattern of arousal suggests that the upper airway mechanoreceptors may play an important role in the induction of an early arousal from nasal occlusion.
Airway Obstruction↗
Treatment of alveolar hypoventilation in a six-year-old girl with intermittent positive pressure ventilation through a nose mask.
Persons with alveolar hypoventilation have abnormal daytime arterial blood gases and abnormal responses to hypercapnia and hypoxia in the absence of any identifiable lung or neuromuscular disease. The underlying defect in the control of breathing has not, however, been confirmed. We studied a 6-yr-old girl who was admitted in respiratory failure after a long history of disturbed breathing awake and asleep, which had been diagnosed as primary alveolar hypoventilation, (PaCO2 = 120). After several days of endotracheal intubation and assisted ventilation, her condition improved and she was extubated. At this time her ventilatory response to hypoxia was absent (VE/SaO2:0.1 l/min/% at a CO2 of 45) and there was a right-shifted response to hypercapnia (VE/PaCO2:2.6 l/min/mmHg). As obstructive sleep apnea was suspected, nocturnal nasal continuous positive airway pressure (CPAP) was tried; however, it was not effective in maintaining arterial oxyhemoglobin saturation. Definite central apneas were observed during sleep both with and without nasal CPAP, and there was an absence of snoring. Her condition deteriorated, and there was a progressive increase in her awake arterial CO2 levels for a period of 4 wk. The IPPV with 5 cm H2O of PEEP was administered through a nose mask during sleep and this maintained both oxygen saturation and transcutaneous CO2 levels within the normal range. After 10 days of nocturnal assisted ventilation, the hypercapnic response returned to the normal position (VE/CO2:2.1 l/min/mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)
Child↗
Nocturnal positive pressure ventilation via a nasal mask.
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Humans↗
Time course of change in ventilatory response to CO2 with long-term CPAP therapy for obstructive sleep apnea.
Nineteen subjects with the obstructive sleep apnea syndrome (10 with daytime arterial CO2 tension 44 mm Hg or higher) were treated with long-term nocturnal continuous positive airway pressure. The ventilatory response to CO2 (Read's method) was measured in triplicate prior to treatment and after 1, 2, 3, 7, and 14 or more nights of therapy. Seven subjects were tested on at least 4 occasions. For each test, slope of the response line and position of the response line (ventilation at a PCO2 of 60 mm Hg) were calculated. The subjects with initial high daytime CO2 showed no change in slope of response with treatment but showed a progressive increase in ventilation at any given degree of PCO2. Ventilation at a PCO2 of 60 mm Hg increased from a mean of 20.0 +/- 1.3 SEM L/min by 8.0 +/- 2.5 SEM L/min after 2 nights of therapy (p less than 0.05, two-way analysis of variance), and by 16.2 +/- 1.9 L/min after 2 wk or more (p less than 0.01). On average, there was no significant change in either slope or position of response in the subjects with initially normal daytime PCO2. We conclude that airway obstruction in sleep (in obstructive sleep apnea syndrome) leads in some subjects to respiratory failure in the daytime, with a left shift in the ventilatory response to CO2, and that this changes is usually reversible during the next several days.
Blood Gas Analysis↗
Treatment of respiratory failure during sleep in patients with neuromuscular disease. Positive-pressure ventilation through a nose mask.
Severe nocturnal hypoxemia may occur in patients with respiratory muscle weakness caused by neuromuscular disorders. Negative pressure ventilators may be partially effective in these patients but can cause upper airway obstructive apneas. We examined the effectiveness of positive pressure ventilation through a nose mask in preventing nocturnal hypoxemia and compared it with negative pressure systems. We reasoned that nasal positive pressure would provide stability for the upper airway. Five patients with neuromuscular disorders underwent a series of all-night sleep studies under control conditions, negative pressure ventilation, and positive pressure ventilation through a comfortable nose mask. Sleep staging and respiratory variables were monitored during all studies. Daytime awake lung function, respiratory muscle strength, and arterial blood gases were also measured. The severe hypoxemia and hypercapnia that occurred under control conditions were prevented by positive pressure ventilation through a nose mask. Negative pressure ventilation improved NREM ventilation in all patients, but did not prevent severe oxyhemoglobin desaturation, which occurred during REM sleep. Negative pressure ventilation appears to contribute to upper airways obstruction during REM sleep as evidenced by cessation of air flow, reduced chest wall movements, falls in arterial oxyhemoglobin saturation, and hypercapnia. With treatment, daytime PaO2 improved from a mean of 70 to 83 mm Hg, and PaCO2 decreased from a mean of 61 to 46 mm Hg. We conclude that nasally applied positive pressure ventilation is a highly effective method of providing nocturnal assisted ventilation because it stabilizes the oropharyngeal airway.
Evaluation Studies as Topic↗
The immediate effects of nasal continuous positive airway pressure treatment on sleep pattern in patients with obstructive sleep apnea syndrome.
We studied the immediate effects of continuous positive airway pressure (CPAP) applied nasally on the pattern of sleep in 12 patients, aged 30-58 years, with obstructive sleep apnea syndrome. All patients demonstrated a moderate to severe syndrome on the control night; apnea index ranged 28-83 apneas/h sleep. Nasal CPAP completely abolished all obstructive apneas and allowed apnea-free breathing in all 12 patients. Nasal CPAP had a marked effect on the sleep pattern. It significantly reduced stage I/II non-rapid eye movement (NREM) sleep and markedly increased stage III/IV NREM and REM sleep on the first treatment night. Stage I/II NREM sleep decreased from a control of 62.7 +/- 2.3% to 29.1 +/- 2.3% on the first treatment night. Stage III/IV NREM sleep increased from a control of 6.7 +/- 1.6% to 31.5 +/- 1.6%. The rebound in this sleep stage was especially marked in 3 patients aged 55-58 years. REM sleep increased from a control of 18.4 +/- 2.0% to 30.6 +/- 2.0% on the first treatment night. There was an increase in REM density. All patients were treated for another 2 nights and their sleep pattern analyzed on the third night. All sleep stages were still significantly different to the control night. The possible mechanisms involved are discussed.
Adult↗
Influence of negative pressure applied to the upper airway on the breathing pattern in unanesthetized awake dogs.
We examined the influence of changes in upper airway pressure on the breathing pattern in 5 unanesthetized awake dogs. The dogs breathed through an endotracheal tube or through a comfortably fitting fiberglass snout mask. With matched resistances and volume of the dead space, the inspiratory duration, tidal volume, and minute ventilation were higher during nasal breathing compared to tracheal breathing. Nasal and tracheal occlusion produced prolongation of inspiration in the first occluded breathing attempt, but the prolongation was more marked in nasal occlusion tests. Augmentation of genioglossus muscle activity occurred on the first occluded breath in nasal but not tracheal occlusion. In another series of experiments, negative pressure was applied to the isolated upper airway while the dog breathed through a tracheostomy tube. Negative pressure caused a prolongation of inspiratory duration which was proportional to the level of the applied pressure. However, the prolongation of inspiratory duration was significantly more marked when application of negative pressure was timed simultaneously with tracheal occlusion. Our results demonstrate that the upper airway has a powerful effect on the control of breathing, which becomes more evident during tracheal occlusion.
Airway Resistance↗
Abnormal pulmonary slowly adapting receptors in canine acrylamide neuropathy.
Slowly adapting lung stretch receptors (SARs) and their vagal afferents are considered to play an important role in the mediation of numerous respiratory reflexes. The understanding of such reflexes has been facilitated by altering the discharge properties of SARs or by preventing the conduction of SAR-generated impulses to the brain stem. In a number of naturally occurring diseases of the peripheral nervous system, the vagus nerve and vagal reflexes are damaged. We have studied the function of SARs in anesthetized dogs with acrylamide neuropathy, a distal axonopathy that has been used as a model of naturally occurring neuropathies. There was a marked increase in threshold and decrease in firing rate of SARs in dogs with moderate neuropathy. Abnormal SAR discharge patterns were observed, and there was a depletion of those units innervated by the fastest conducting vagal afferent fibers in treated animals. Acrylamide induced degeneration of myelinated fibers in bronchial branches of the vagus nerve. These abnormalities were partially reversed upon withdrawal of the neurotoxin. Acrylamide may be a useful agent in the study of vagally mediated respiratory reflexes. SAR function is likely to be abnormal in diseases of the peripheral nervous system.
Acrylamide↗
Upper airway dilating forces during wakefulness and sleep in dogs.
We measured the pressure within an isolated segment of the upper airway in three dogs during wakefulness (W), slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. Measurements were taken from a segment of the upper airway between the nares and midtrachea while the dog breathed through a tracheostoma. These pressure changes represented the sum of respiratory-related forces generated by all muscles of the upper airway. The mean base-line level of upper airway pressure (Pua) was -0.5 +/- 0.03 cmH2O during W, increased by a mean of 2.1 +/- 0.2 cmH2O during SWS, and was variable during REM sleep. The mean inspiratory-related phasic change in Pua was -1.2 +/- 0.1 cmH2O during wakefulness. During SWS, this phasic change in Pua decreased significantly to a mean of -0.9 +/- 0.1 cmH2O (P less than 0.05). During REM sleep, the phasic activity was extremely variable with periods in which there were no fluctuations in Pua and others with high swings in Pua. These data indicate that in dogs the sum of forces which dilate the upper airway during W decreases during SWS and REM sleep. The consistent coupling between inspiratory drive and upper airway dilatation during wakefulness persists in SWS, but is frequently uncoupled during REM sleep.
Animals↗
Reversal of central sleep apnea using nasal CPAP.
Based on the theory that obstructive (OSA) and central (CSA) sleep apneas share common pathophysiologic mechanisms, we attempted to treat eight patients with predominantly CSA by continuous positive airway pressure (CPAP). All patients exhibited repetitive episodes of CSA and mixed sleep apneas (MSA) in the supine position with a mean duration of 23.7 +/- 0.7 s and 34.5 +/- 1.3 s, respectively. The pattern of apnea changed when the subject lay in the lateral position. Five patients were observed to develop OSA in the lateral position with a mean duration of 27.2 +/- 1.5 s, while the other three patients snored continuously. High levels of CPAP (range 9.0 to 16.5 cm H2O) prevented all CSA and MSA and resulted in quiet breathing in all eight patients. Intermediate levels of CPAP produced firstly MSA, then purely OSA and/or continuous snoring. Low levels of nasal CPAP also prevented OSA and snoring occurring in the lateral posture in all subjects (range 2.0 to 8.3 cm H2O). Three patients are currently on home CPAP therapy for a range of four to 36 months. We conclude that upper airway collapse in the supine posture has a key role in the induction of CSA. We suggest that a reflex inhibition of respiration through activation of supraglottic mucosal receptors during passive oropharyngeal airway closure caused CSA in these patients.
Adult↗
Nanosecond fluctuations of the molecular backbone of collagen in hard and soft tissues: a carbon-13 nuclear magnetic resonance relaxation study.
We have determined the amplitude of nanosecond fluctuations of the collagen azimuthal orientation in intact tissues and reconstituted fibers from an analysis of 13C NMR relaxation data. We have labeled intact rat calvaria and tibia collagen (mineralized and cross-linked), intact rat tail tendon and demineralized bone collagen (cross-linked), and reconstituted lathyritic (non-cross-linked) chick calvaria collagen with [2-13C]glycine. This label was chosen because one-third of the amino acid residues in collagen are glycine and because the 1H-13C dipolar coupling is the dominant relaxation mechanism. Spin-lattice relaxation times (T1) and nuclear Overhauser enhancements were measured at 15.09 and 62.98 MHz at 22 and -35 degrees C. The measured NMR parameters have been analyzed by using a dynamic model in which the azimuthal orientation of the molecule fluctuates as a consequence of reorientation about the axis of the triple helix. We have shown that if root mean square fluctuations in the azimuthal orientations are small, gamma rms much less than 1 rad, the correlation function decays with a single correlation time tau and T1 depends only upon tau and gamma rms and not the detailed model of motion. Our analysis shows that, at 22 degrees C, tau is in the 1-5-ns range for all samples and gamma rms is 10 degrees, 9 degrees, and 5.5 degrees for the non-cross-linked, cross-linked, and mineralized samples, respectively. At -35 degrees C, gamma rms is less than 3 degrees for all samples. These results show that mineral and low temperature significantly restrict the amplitude of nanosecond motions of the collagen backbone.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Respiratory muscle activity and thoracoabdominal motion during acute episodes of asthma during sleep.
To understand the mechanisms of respiratory system compensation to internal loading during sleep, all-night sleep studies were performed in 10 patients with chronic stable asthma. We used noninvasive measurements to identify the onset of increased airway resistance in sleep. In each sleep study, we recorded arterial oxygen saturation (SaO2) and an array of electromyograms (diaphragm, external intercostal and sternomastoid) as well as thoracoabdominal motion. Only 4 patients developed acute asthma during sleep. A total of 6 such attacks were recorded. The attacks were detected by audible wheeze, augmentation of diaphragm, external intercostal and sternomastoid activity, associated with distinctive changes in thoracoabdominal motion. The duration of these acute asthmatic attacks ranged between 20 and 140 min. One attack started in stage I/II non-rapid-eye-movement (NREM) sleep, 3 in stage III/IV NREM sleep, and 2 in rapid-eye-movement (REM) sleep. Acute asthma in NREM sleep resulted in a paradoxical inward displacement of the abdomen during early inspiration. Attacks occurring during REM sleep resulted in rib cage inward displacement during inspiration. Attacks occurring during REM sleep resulted in rib cage inward displacement during inspiration. Attacks occurring in both NREM and REM sleep did not result in a significant fall in SaO2. We conclude that acute internal respiratory loading during sleep can provoke different compensatory mechanisms in order to provide adequate ventilation in adult asthmatics.
Abdominal Muscles↗
Obstructive sleep apnea.
This chapter provides an account of obstructive sleep apnea that is designed for clinicians. Current ideas about the mechanism of upper airway obstruction are reviewed, and the clinical features are discussed in a manner intended to facilitate the clinical assessment of such patients. Various forms of treatment are reviewed, with major emphasis given to the use of nasal positive airway pressure, a form of therapy developed by the authors.
Airway Obstruction↗
Detection of cis and trans X-Pro peptide bonds in proteins by 13C NMR: application to collagen.
Heretofore the complexity of natural abundance spectra has precluded the use of 13C NMR to detect cis peptide bonds in proteins. We have incorporated [4-13C]proline into chicken calvaria collagen and report here well-resolved C gamma signals, arising from cis and trans X-Pro and X-Hyp peptide bonds (where X is any amino acid residue) in the 13C NMR spectrum of the thermally unfolded protein. Measurement of 13C signal areas shows that 16% of the X-Pro and 8% of X-Hyp bonds are cis in the unfolded collagen. These results strongly support the conclusion drawn from kinetic studies that cis-trans isomerization of peptide bonds is the rate-limiting step in helix propagation after nucleation. Our method can be applied to other proteins as well and should aid in testing the generality of the hypothesis of Brandts, Halvorson, and Brennan that cis-trans isomerization is the rate-limiting step in protein folding when proline is present.
Animals↗
Ventilation and arousal responses to hypercapnia in normal sleeping humans.
We measured arousal and ventilatory responses to rebreathing from a small bag, initially approximately 7% CO2 in 40% O2, via a nose mask in 13 normal human adults. With deepening non-rapid-eye-movement sleep (NREM), males aroused at increasing alveolar PCO2 (mean +/- SE: stage II 58.6 +/- 1.7, stage III 61.2 +/- 1.0, stage IV 63.8 +/- 0.8 Torr), whereas in rapid-eye-movement sleep (REM), arousal alveolar PCO2 was 57.7 +/- 0.7 Torr, i.e., much lower than in stage III and IV NREM. Females showed no significant change in arousal alveolar PCO2, (II 57.6 +/- 0.9, III 57.3 +/- 1.3, IV 59.4 +/- 0.9, REM 56.3 +/- 1.0 Torr). Male ventilatory response was 2.5 +/- 0.1 (SE) 1 X min-1 X Torr-1 and fell by 49% in NREM (1.29 +/- 0.13) and by 69% in REM (0.78 +/- 0.18). Female response was little affected by state, being similar to male NREM response (wake 1.39 +/- 0.14, NREM 1.40 +/- 0.13, REM 1.11 +/- 0.26 1 X min-1 X Torr-1). In NREM tests, there was no change in sleep state until arousal, whereas in REM, subjects awoke abruptly with the onset of rebreathing (11 cases), showed a transient arousal with onset but continued in REM until final arousal (21 cases), or changed to NREM at onset (2 cases). These arousal results contrast sharply with findings in tracheostomized dogs and in obstructive sleep apnea syndrome, where asphyxic arousal is later in REM than in NREM, suggesting that the events at test onset in REM in the present study may be related to upper airway sensitivity to CO2 specific to REM.
Adult↗