Biomedical subjects

D W Hudgel

Publications and source records attributed to D W Hudgel.

At least 19 recordsLinked to original sources

PubMed1996

Results of a multicenter study of nebulized inhalant bronchodilator solutions.

The efficacy, persistence of bronchodilator action, and safety of the quaternary ammonium anticholinergic agent, ipratropium bromide (500 microgram), and placebo were compared when each was added in solution form to the beta-adrenergic agonist solution, metaproterenol sulfate (15 mg), and administered three times daily for 12 weeks to a total of 213 patients with chronic obstructive pulmonary disease (COPD). Subjects had a mean forced expiratory volume in 1 second (FEV1) of approximately 1 liter (37% of predicted) and were permitted to use nonanticholinergic therapy for COPD throughout the trial. The study was a randomized, double-blind, 85-day, parallel-group, eight-center study. On a 3 test days, 1, 43, and 85, mean peak responses for FEV1 and forced vital capacity and mean area under the curve were significantly higher for the iprathropium bromide-metaproterenol combination than for metaproterenol only. Duration of action was also significantly longer for the combination therapy than for the beta-agonist alone on test days 1 and 43. Neither treatment regimen produced an demonstrable effect on daily morning peak expiratory flow rates, reported respiratory symptoms, or quality of life. Both treatment regimens were similarly well tolerated with a comparable frequency of adverse events. These results suggest that the combination of iprathropium bromide and metaproterenol inhalation solutions offers a potential therapeutic advantage to patients with symptomatic COPD over nebulized metaproterenol alone without the risk of increased side effects.

Administration, Inhalation↗

PubMed1996

Hypoglossal and phrenic motoneuron responses to serotonergic active agents in rats.

5-Hydroxytryptamine (serotonin, 5-HT) affects upper airway and chest wall inspiratory muscle control. The purpose of this study was to investigate the relative interaction of serotonergic agents on these two muscle groups. We measured the responses of the hypoglossal and phrenic nerves to the systemic administration of serotonergic-active agents and determined the receptor types through which these agents act in anesthetized, vagotomized, paralyzed and artificially ventilated rats. The serotonin precursor, L-5-hydroxytryptophan (L-5-HTP) produced equivalent stimulation of phasic inspiratory activity of the hypoglossal and phrenic nerves. General serotonin antagonists produced significant and equivalent diminution of both motoneuron pools. Specific 5-HT1A stimulation and 5-HT1C/2 antagonism enhanced ventilatory activity. We conclude: (1) a baseline level of serotonergic input to hypoglossal and phrenic motoneuron pools was present, (2) different 5-HT receptors had different effects on ventilatory neural activity, and (3) hypoglossal and phrenic motoneuron pools responded similarly to the serotonergic agents given.

5-Hydroxytryptophan↗

PubMed1996

Treatment of obstructive sleep apnea. A review.

Treatment of obstructive sleep apnea (OSA) has developed over the last 25 years from tracheostomy to a variety of options, including weight loss, nasal continuous positive airway pressure (N-CPAP), pharyngeal surgery, and medications. None of these options is definitive or curative, except possibly weight loss. The most widely prescribed treatment is N-CPAP, but recently published studies using objective measurement of patient compliance show less than ideal compliance. Attempts have been made to design pharyngeal surgery according to the site of upper airway collapse or narrowing, as identified by various techniques in wakefulness. How representative these studies are of upper airway physiology in sleep is questionable. Recent studies have shown improved surgical success in correcting OSA. However, disturbing data are available in a limited number of patients that demonstrate worsening of the OSA months after a favorable response to surgery. More studies assessing the long-term outcome of pharyngeal surgery are needed. Several pharmacologic agents have been used to treat OSA. Results with any particular agent are not better than with N-CPAP or surgery. However, studies of subgroups of patients with OSA in which a particular pharmacologic agent may be specifically indicated, such as thyroxine in hypothyroidism, have not been conducted (to our knowledge). An algorithm for the approach to treatment recommendations is presented. Basic to this algorithm is an objective presentation of therapeutic options to the patient with OSA and a respect for the patient's preferences.

Humans↗

PubMed1995

Ventilatory stability to CO2 disturbances in wakefulness and quiet sleep.

Oscillatory ventilatory pattern occurs more frequently in sleep despite the stabilizing factor of sleep-induced reduction in CO2 chemosensitivity. In nine young normal humans, we have tested the hypothesis that, despite a sleep-induced reduction in chemosensitivity, the transient central chemoreceptor-mediated change inspiratory ventilation (VI) caused by a standardized disturbance to chemoreflex ventilatory control is similar in quiet sleep and wakefulness. The equivalent VI response to a single-breath hyperoxic hypercapnic stimulus (i.e., inhaling a single breath of 0.01 liter of CO2 in O2--a direct measure of "closed-loop" dynamic response) was determined using pseudorandom binary CO2 stimulation and the prediction-error method of transfer function estimation. From these data, the response of VI to a single-breath increase of 1 Torr in end-tidal PCO2 was also derived, from which "dynamic" central chemosensitivity was calculated. Despite a 43% reduction in dynamic central chemosensitivity, the peak and the area under the closed-loop VI response are similar in wakefulness and quiet sleep, whereas sleep increases the duration of the response by 48%. Thus hyperoxic ventilatory stability is not reduced in quiet sleep relative to wakefulness. We propose that changes in dynamics of pulmonary gas exchange in sleep substantially offset the decreased chemosensitivity, thereby maintaining the gains and time constants of the central chemoreceptor-mediated component of the closed-loop ventilatory control system similar to those during wakefulness.

Adult↗

PubMed1995

Continuous versus bilevel positive airway pressure for obstructive sleep apnea.

Recent objective studies demonstrate relatively low hours of nightly use during nasal continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea (OSA). Patients frequently complain of dyspnea or discomfort during CPAP use, especially during expiration (against the continuous pressure), which may be a reason for the low hours of use. We hypothesized that with decreased expiratory pressure, hours of nightly use would increase. Therefore, we randomized 83 OSA patients to receive either continuous or bilevel positive airway pressure when expiratory pressure is lower. To document objectively the effective use of either therapy, we built and installed elapsed-time and mask pressure sensors in the patients' positive airway pressure units. A total of 62 patients were evaluable and followed for 1 yr. Of these, 26 received bilevel and 36 CPAP pressures. The machine timers measured accumulated "machine-on" time, and the mask pressure sensor recorded the total time in which the mask pressure was within 2 cm H2O of the effective pressure (pressure shown to eliminate 95% of the obstructive apneas during a full night of polysomnography). The mean machine timer hours of CPAP were 5.0 +/- 0.19 SEM and 4.9 +/- 0.23 SEM during bilevel therapy (p NS) over a 12-mo period. The pressures required during CPAP or bilevel therapy were not different between high and low hourly users. Effective use, the percentage of time that the machine was running and the prescribed pressure was being delivered, was 80% in CPAP and 82% in the bilevel users (p NS). Both groups had equal complaints with regard to mask discomfort, machine noise, and nasal stuffiness.(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗

PubMed1995

Abnormal serotonergic stimulation of cortisol production in obstructive sleep apnea.

Because serotonin (5-HT) precursor or reuptake inhibitors improve obstructive sleep apnea (OSA), we hypothesized that brain serotonergic activity may be decreased in OSA. To test this hypothesis, we measured the cortisol response to the ingestion of L-5-hydroxytryptophan (L-5-HTP), a 5-HT precursor that is decarboxylated to 5-HT in the brain. Either L-5-HTP or an identical-looking placebo was administered at 0800, and blood was obtained over the following 4 h for serum cortisol determination. A placebo-controlled ACTH stimulation test was performed to evaluate adrenal function. We found that a group of 11 OSA patients had significantly higher cortisol production after L-5-HTP administration compared with a group of 11 control nonapneic subjects. The pretest cortisol levels and ACTH stimulation test results were not different between the two groups. We conclude that the cortisol response to L-5-HTP was elevated in the OSA patients studied, most likely as a result of increased hypophyseal 5-HT activity. We speculate that the 5-HT postsynaptic receptors that induce corticotropin releasing factor production and release are upregulated, or supersensitized, as a result of a brain 5-HT-deficient state that exists during sleep in OSA. We anticipate that medullary serotonergic neurons that affect ventilation would be altered similarly.

5-Hydroxytryptophan↗

PubMed1995

Pharmacologic treatment of obstructive sleep apnea.

From this review it is obvious that no one pharmacologic agent is universally useful in the treatment of OSA. However, as mentioned in the introductory remarks above, the expectation of beneficial results in a heterogenous population of patients with OSA by specific-acting pharmacologic agents may be somewhat irrational. In addition to this problem, studies performed to date are often not controlled and are usually investigations in small numbers of subjects. However, from the data produced it is apparent that OSA precipitated by endocrinologic problems will improve with hormone replacement. Medroxyprogesterone has been shown to be especially useful in patients with an obesity-hypoventilation component to their disease. Protriptyline may also be useful, but its usefulness is impaired by significant adverse effects. Most likely, both medroxyprogesterone and protriptyline would be more tolerable in female OSA patients, but unfortunately, most of the OSA patient groups studied to date have been composed exclusively of male subjects. Therefore, we do not know if these agents would be more effective and better tolerated in female patients with OSA. The roles of ACE inhibitors and buspirone are not yet established. Serotonin-active agents may be useful in some patients with OSA, but the characteristics of responders are not defined for appropriate patient selection. Much work remains ahead to identify effective pharmacologic agents for OSA. Once identified, these agents must be tested in representative patient groups with a double-blind, placebo-controlled study design in multicenter trials to test the value of these agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Endocrine System Diseases↗

PubMed1994

Respiratory muscle activity during sleep-induced periodic breathing in the elderly.

During spontaneous sleep-induced periodic breathing in elderly subjects, we have found that tidal volume oscillations are related to reciprocal oscillations in upper airway resistance. The purpose of this study was to address the mechanism of the relationship between oscillations in tidal volume and upper airway resistance in elderly subjects with sleep-induced periodic breathing. We hypothesized that the spontaneous periodic breathing observed in non-rapid-eye-movement (NREM) sleep in elderly subjects would be closely related to fluctuations in upper airway resistance and not to changes in central motor drive to ventilatory pump muscles. Therefore, in eight healthy elderly subjects, we measured costal margin chest wall peak moving time average electrical inspiratory activity (CW EMG), ventilation variables, and upper airway resistance during sleep. Five of eight subjects had significant sine wave oscillations in upper airway resistance and tidal volume. For these five subjects, there was a reciprocal exponential relationship between peak upper airway inspiratory resistance and tidal volume or minute ventilation [r = -0.60 +/- 0.20 (SD) (P < 0.05) and -0.55 +/- 0.26 (P < 0.05), respectively], such that as resistance increased, ventilation decreased. The relationship between CW EMG and tidal volume or minute ventilation was quite low (r = 0.12 +/- 0.32 and -0.07 +/- 0.27, respectively). This study demonstrated that oscillations in ventilation during NREM sleep in elderly subjects were significantly related to fluctuations in upper airway resistance but were not related to changes in chest wall muscle electrical activity. Therefore, changes in upper airway caliber likely contribute to oscillations in ventilation seen during sleep-induced periodic breathing in the elderly.

Aged↗

PubMed1993

The carotid body in the motorneuron response to protriptyline.

Protriptyline (PRT) has been shown to preferentially stimulate upper airway inspiratory motorneurons relative to phrenic activity in hyperoxic hypercapnia in the decerebrate cat via a carotid body-independent mechanism. Since previous studies indicated that carotid body stimulation results in preferential activation of upper airway respiratory muscles during both hypercapnia and hypoxemia, we hypothesized that if PRT preferentially stimulated upper airway motorneurons, the mechanism of action might involve the carotid body. We investigated the effect of PRT on carotid body function by comparing the electrical activity of the hypoglossal (HYP) with that of the phrenic (PHR) nerve in carotid sinus nerve intact (CSNI) and CSN-sectioned (CSNX) anesthetized rats, before and after PRT (0.5 mg/kg i.v.), during 100% O2, 15% O2 (N2 balance), and 4% CO2 (O2 balance) administration. The moving time average (MTA) peak inspiratory electroneurogram activities of both the HYP and PHR nerves increased an equivalent amount after PRT injection during hyperoxia, in both CSNI and CSNX rats. During hypoxia, the HYP activity increased significantly more than the PHR activity only in CSNI rats after PRT injection. During hyperoxic hypercapnia, HYP MTAs increased a similar amount in the CSNI and CSNX rats. We conclude that the HYP and PHR respiratory motorneuron pool responses to PRT depend on the blood gas status at the time of drug administration.

Animals↗

PubMed1993

Pattern of breathing and upper airway mechanics during wakefulness and sleep in healthy elderly humans.

Elderly subjects are known to be prone to periodic breathing in sleep. Because periodic breathing may be associated with changes in upper airway caliber, we hypothesized that oscillations in upper airway caliber contribute to the increased prevalence of sleep-related periodic breathing in the elderly. We tested this hypothesis by measuring upper airway resistance, ventilatory variables, and the pattern of variation of these variables in groups of body size-matched young and elderly healthy individuals during wakefulness and stage 2 non-rapid-eye-movement sleep. No major differences existed between the two groups during either wakefulness or sleep in mean upper airway resistance or ventilation values. However, ventilation was more variable during sleep in the elderly; this variability was oscillatory in the majority of elderly subjects at an average rate of 0.04 breaths/cycle or one cycle approximately every 24 s. Oscillations in upper airway resistance during sleep were associated with reciprocal oscillations in tidal volume and/or minute ventilation at the same frequency. Those subjects who had significant oscillations in upper airway resistance had more apneas and hypopneas than those subjects without such oscillations. Oscillations in resistance and ventilation occurred in the supine but not in the lateral body position. We conclude that the wide oscillations in upper airway resistance present during sleep in supine healthy elderly subjects produce a fluctuating mechanical limitation of ventilation, which may contribute to periodic breathing.

Adult↗

PubMed1993

Adaptive buffering of breath-by-breath variations of end-tidal CO2 of humans.

We have designed and implemented a computer-controlled system that uses an adaptive control algorithm (generalized minimum variance) to buffer the breath-by-breath variations of the end-tidal CO2 fraction (FETCO2) that occur spontaneously or are exaggerated in certain experimental protocols (e.g., induced hypoxia, any type of induced variations in the ventilatory pattern). Near the end of each breath, FETCO2 of the following breath is predicted and the inspired CO2 fraction (FICO2) of the upcoming breath is adjusted to minimize the difference between the predicted and desired FETCO2 of the next breath. The one-breath-ahead prediction of FETCO2 is based on an adaptive autoregressive with exogenous inputs (ARX) model: FETCO2 of a given breath is related to FICO2, FETCO2 of the previous breath, and inspiratory ventilation. Adequacy of the prediction is demonstrated using data from experiments in which FICO2 was varied pseudorandomly in wakefulness and sleep. The algorithm for optimally buffering changes in FETCO2 is based on the coefficients of the ARX model. We have determined experimentally the frequency of FETCO2 variations that can be buffered adequately by our controller, testing both spontaneous variations in FETCO2 and variations induced by hypoxia in young awake human subjects. The controller is most effective in buffering variations of FETCO2 in the frequency range of <0.1 cycle/breath. Some potential applications are discussed.

Adaptation, Physiological↗

PubMed1993

Mechanism of sleep-induced periodic breathing in convalescing stroke patients and healthy elderly subjects.

Cerebral vascular ischemic strokes are known to precipitate Cheyne-Stokes periodic breathing. Interestingly, Cheyne-Stokes-like breathing during sleep may be associated with obstructive sleep apnea (OSA) in some individuals. Therefore, it was reasoned that stroke patients with periodic breathing in sleep would be susceptible to OSA. Because oscillations in upper airway resistance can occur as a component of sleep-induced periodic breathing, we hypothesized that stroke patients with sleep-induced periodic breathing would have oscillations in upper airway resistance. These oscillations in resistance would be expected to contribute to OSA. We studied stroke patients with sleep-induced periodic breathing and control subjects to evaluate the relationship between upper airway resistance and ventilation in periodic breathing in sleep. Ventilation and upper airway resistance were measured in presleep wakefulness and in stage 2 NREM sleep. Mean tidal volume, minute ventilation, respiratory cycle timing variables, and upper airway resistance were not different between stroke and control subjects, either awake or asleep. Upper airway resistance increased and ventilation volume decreased from wakefulness to sleep in both groups. In an equivalent number of subjects from each group, reciprocal patterned oscillations in tidal volume and upper airway resistance were present at a 5 to 12.5 breath frequency during sleep. As upper airway resistance increased, tidal volume decreased. Stroke patients had wider fluctuations in upper airway resistance than control subjects, likely contributing to the higher number of sleep-disordered breathing events observed in the stroke patients.

Aged↗

PubMed1993

Properties of the upper airway during sleep.

Research efforts to date have identified that both anatomic and physiologic variables may contribute to the pathophysiology of obstructive sleep apnea. Whether specific factors within either of these two categories will be shown to predominate remains to be seen. Surely, experience with sleep apnea patients teaches us that different variables are important in different OSA patients. In the area of anatomy, investigators are just beginning to try surgical approaches designed specifically for the pharyngeal site of obstruction found in a given patient. Possible new physiologic and pharmacologic treatments are being explored. Hopefully, such treatments will be as effective and more convenient than continuous positive airway pressure.

Humans↗

PubMed1992

Mechanisms of obstructive sleep apnea.

This article has reviewed the anatomic, compliance, reflex, and respiratory muscle variables that affect upper airway caliber and abnormalities which may precipitate upper airway collapse during sleep. One or more of these variables may be important in the mechanism of OSA in any given patient. First, anyone with anatomic narrowing of the upper airway is susceptible to OSA. However, we do know if anatomic narrowing of the upper airway is necessary for the development of OSA. Surely, heavy snoring produces pharyngeal trauma and possibly edema or inflammation, which in turn may narrow the upper airway. Submucosal adipose tissue or cervical adipose tissue may compress the airway when the tonic electrical activity of the pharyngeal muscles decreases with sleep onset. Data reviewed support the idea that the upper airway of OSA patients may be more collapsible than the upper airway of nonapneic subjects. Intrinsic tissue abnormalities have not been demonstrated that might be responsible for this collapsibility. Changes in collapsibility found are consistent with, and may be due to, changes in tonic and phasic contraction of upper airway muscles. Abnormalities in reflexes affecting upper airway size surely might exist in OSA. Edema or inflammation of pharyngeal tissues might not only narrow the upper airway but might also impair normal function of the receptors responsible for initiating protective reflexes. We propose the fluctuation between a low- and a high-drive state contributes to upper airway collapse in OSA. With this fluctuation the balance of forces and critical pressure concepts discussed above come into play (Fig 6). By stimulating upper airway inspiratory muscles, CO2 eliminates the hypoapneic, low-drive, high-resistance periods and thereby reduces the number of apneas. In addition, preferential stimulation of upper airway muscle activity dilates the upper airway per se. If the relative value of each of these factors can be determined diagnostically, perhaps therapy can be made more specific. By being more specific, therapy should be more successful than the present practice of prescribing a particular therapy, regardless of the specific mechanism responsible for the OSA in a given patient.

Humans↗

PubMed1992

The role of upper airway anatomy and physiology in obstructive sleep apnea.

Research efforts to date have determined that both anatomic and physiologic variables may contribute to the pathophysiology of OSA. Whether specific factors within either of these two categories will be shown to predominate remains to be seen. Surely, experience with sleep apnea patients teaches us that different variables are important in different OSA patients. However, even those patients who initially appear to have predominantly an anatomic or physiologic cause of their OSA often fail to respond to specific treatment. Treatment failure implies the following: (1) The initial impression of the importance of a given variable was wrong. This may happen in the patient who has a narrow transpalatal airway and fails to respond to uvulopalatopharyngoplasty. In this individual, physiologic variables such as pharyngeal collapsibility or periodic breathing may need to be addressed. Of course, the reverse may occur; patients may be treated pharmacologically for an assumed physiologic mechanism and important anatomic factors may have been overlooked. Our ability to differentiate the importance of these different variables is poor. Therefore, our diagnostic acumen needs further refinement. (2) Of course, it is likely that the proper diagnosis was made, but the therapy chosen was imperfect. In the area of anatomy, investigators are just beginning to try surgical approaches designed specifically for the pharyngeal site of obstruction. In other words, uvulopalatopharyngoplasty is not the best approach for everyone. In physiology, treatments beyond continuous positive airway pressure will be needed. It is hoped that advances in the pharmacology of sleep disorders will establish more convenient and successful therapies. It is likely that OSA is a heterogenous disease process. We must realize that a treatment that helps one patient may not be applicable to the next individual. Through a better understanding of the pathophysiology of OSA, better treatment modalities should be developed, resulting in improved quality of life for OSA patients.

Humans↗

PubMed1991

Evaluation of the upper airway in patients with obstructive sleep apnea.

Multiple methods have been used to study the structure and physiological behavior of the upper airway (UA) in patients with obstructive sleep apnea (OSA). Valuable information may be obtained from the physiologic measurement of pressure and resistance along the UA, as well as from imaging techniques that include: direct or fiberoptic visualization, cephalometric roentgenograms, fluoroscopy, acoustic reflection, computerized tomography, and magnetic resonance imaging. This review summarizes the information that each of these methods has contributed to our understanding of the UA. The results obtained with these different methodologies have generally been complementary with structural narrowing being identified in the majority of patients with OSA. This narrowing is usually focal and located in the velopharyngeal or retropalatal segment of the UA. This is also the predominant site of initial UA collapse. Although obesity with enlargement of soft tissue structures is considered the predominant mechanism leading to UA narrowing, abnormal craniofacial development on a genetic or developmental basis plays an important contributory role.

Airway Obstruction↗

PubMed1991

Uvulopalatopharyngoplasty in obstructive apnea. Value of preoperative localization of site of upper airway narrowing during sleep.

We hypothesized that those obstructive sleep apnea (OSA) patients with upper airway collapse during sleep within the transpalatal airway would have a more favorable response to uvulopalatopharyngoplasty (UPP) than those patients with obstruction within the hypopharyngeal airway. We tested this hypothesis in seven OSA patients with transpalatal and seven with hypopharyngeal obstruction undergoing UPP. Preoperatively the apnea/hypopnea index (AHI) was different between palatal and hypopharyngeal obstructors, 37.8 +/- 6.0 (+/- SEM) and 63.9 +/- 6.3, respectively (p less than 0.05), but the apnea-associated arterial oxygen desaturation and the lowest sleep saturation level were not different between the two groups. Postoperatively the AHI was 17.6 +/- 7.2 in the palatal obstructors and 40.3 +/- 15.6 in the hypopharyngeal obstructors (both p less than 0.05 from preoperative AHI). The palatal obstructors had a significant decrease in the percentage of sleep time spent apneic and the hypopharyngeal obstructors had a significant decrease in the hypopnea, but not apnea, time following surgery. The palatal obstructors had a significantly higher postoperative arterial oxygen saturation than the hypopharyngeal obstructors. Two hypopharyngeal obstructors worsened postoperatively. In addition we found that regardless of the site of the obstruction preoperatively, all obstructions occurred at the level of the palate postoperatively. We conclude that patients with preoperative transpalatal obstruction had diminution in obstructive apneas and those with hypopharyngeal obstruction had diminution in hypopneas but not apneas. Oxygenation was better postoperatively in the palatal obstructors, and none worsened postoperatively. These results suggest that identification of the site of upper airway obstruction in OSA may be beneficial.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Response of obstructive sleep apnea to fluoxetine and protriptyline.

Protripyline is the pharmacologic agent most commonly used to treat obstructive sleep apnea (OSA); however, its anticholinergic side effects make it intolerable to many patients. Because serotonin may be a central respiratory stimulant and because the serotonin-uptake inhibitor, fluoxetine, is usually well tolerated, we wanted to try fluoxetine in the treatment of OSA. Therefore, we compared the effect of fluoxetine to that of protriptyline in 12 patients with OSA. Both drugs significantly decreased the proportion of REM sleep time and decreased the number of apneas or hypopneas in NREM sleep. The response to fluoxetine was equivalent to that of protriptyline; however, for the group as a whole, there was no significant improvement in the number of arterial oxygen desaturation events, the level of arterial oxygen desaturation, or the number of arousals with either agent. Although there was wide variability in the response to each medication, six of the 12 patients had good responses, including improvement in oxygenation, to either fluoxetine or protriptyline. Three patients could not complete the trial of protriptyline. We conclude that fluoxetine is beneficial to some, but not all, patients with OSA. Fluoxetine was better tolerated than protriptyline.

Adult↗