A new method for the remote collection of nasal and exhaled nitric oxide.

STUDY OBJECTIVES: The present study introduces a method that has been developed to improve the remote collection and transportation of gas samples from the nose and lungs. DESIGN: Assessment of agreement between two methods of clinical measurements. SETTING: Noninvasive exhaled gas measurement at a respiratory research laboratory. PARTICIPANTS: Ten nonsmoking adult volunteers (median age, 44 years; age range, 33 to 53 years; men, 6; women, 4) were recruited. MEASUREMENTS AND RESULTS: Exhaled nitric oxide (ENO) and nasal nitric oxide (NNO) outputs were measured directly (on-line) and remotely (off-line). With the velum closed, lung air was exhaled at fixed flows (ie, 6, 8, and 10 L/min) (ENO) or room-air was aspirated through the nose in series at one fixed flow (ie, 5 to 8 L/min) (NNO). The off-line nitric oxide (NO) measurements were achieved by a gas collection tube system, which consisted of a flow control unit, a tube reservoir with one-way valves at both ends, and an interrupter valve allowing the trapping of gas inside the tube and eliminating the inclusion of "dead space." After clamping, the reservoir may store and transport the gas samples for delayed analysis. The coefficient of variation of three consecutive NO measurements was < 3% for both on-line and off-line ENO and NNO. The correlations between on-line and off-line measurements in both ENO and NNO outputs were high (r = 0.99; R(2) = 0.99), and, unlike previous studies using bag-collection, the ENO outputs for on-line and off-line measurements were in good agreement (Bland-Altman test) at all flows tested. CONCLUSIONS: The tube gas collection system eliminates the dead space and contamination during the gas sampling and permits the cost-effective and reliable off-line collection of both nasal and exhaled gas samples.

Nasal nitric oxide and the nasal cycle.

OBJECTIVES: To establish the relationship between nasal patency and the nitric oxide (NO) concentration in the nasal airways. METHODS: Unilateral nasal NO concentration (n = 11) and inhaled nasal NO concentration at oropharynx (n = 9) were measured in healthy adult volunteers. Subjects breathed normally through the nose with a known resistance (ranged from none to total occlusion) placed in one nostril. In a subgroup (n = 7), the unilateral nasal NO concentrations were determined with nasal cavity congestion induced by lateral decubitus. RESULTS: When the added nasal resistance was less than 6 cm H(2)0 per liter per second, the peak NO concentrations in the nose remained below 80 parts per billion (ppb). Thereafter, the higher the resistance, the greater the NO concentration. It was up to 1109.7 ppb when the front nostril was totally occluded. There was no correlation between oropharyngeal NO concentrations and resistance in the front of the nose (r = 0.4). There was a significantly negative correlation between nasal cavity volumes and nasal NO concentrations (r = -0.8, P <.001). CONCLUSIONS: Increases in nasal resistance to levels encountered in the nasal cycle and in recumbency augments the NO concentration within the obstructed side of the nose. Although that within the nose changes with patency, the NO concentration is constant down to the lower airways. The modulation role of the upper airways to the inhaled NO concentration remains unclear.

Nitric oxide in the nasal airway: a new dimension in otorhinolaryngology.

The discovery that the gas nitric oxide (NO) is an important signaling molecule in the cardiovascular system earned its Nobel prize in 1998. NO has since been found to play important roles in a variety of physiologic and pathophysiologic processes in the body including vasoregulation, hemostasis, neurotransmission, immune defense, and respiration. The surprisingly high concentrations of NO in the nasal airway and paranasal sinuses has important implications for the field of otorhinolaryngology. NO provides a first-line defense against micro-organisms through its antiviral and antimicrobial activity and by its upregulation of ciliary motility. Nasal treatments such as polypectomy, sinus surgery, removal of hypertrophic adenoids and tonsils, and treatment of allergic rhinitis may alter NO output and, therefore, the microbial colonization of the upper airways. Nasal surgery aimed at relieving nasal obstruction may do the same but would also be expected to improve pulmonary function in patients with asthma and upper airway obstruction. NO output rises in a number of conditions associated with chronic airway inflammation, but not all of them. Concentrations are increased in asthma, allergic rhinitis, and viral respiratory infections, but reduced in sinusitis, cystic fibrosis, primary ciliary dysfunction, chronic cough, and after exposure to tobacco and alcohol. Therefore, NO, similar to several other inflammatory mediators, probably subserves different functions as local conditions dictate. At present, it seems that the measurement of NO in the upper airway may prove valuable as a simple, noninvasive diagnostic marker of airway pathologies. The objective of this review is to highlight some aspects of the origin, physiology, and functions of upper airway NO, and to discuss the particular methodological problems that result from the complex anatomy.

Upper airway pressures in snorers and nonsnorers during wakefulness and sleep.

OBJECTIVE: To compare upper airway pressures in snorers and nonsnorers during sleep and wakefulness. DESIGN: Case series of snorers and nonsnoring controls. SETTING: Sleep clinic of a university hospital. METHODS: We used open catheters to measure differential nasopharyngeal and hypopharyngeal pressures in 8 nonapneic snorers with excessive daytime tiredness and 10 healthy nonsnoring controls. Measurements were performed during sleep (with the mouth taped to ensure exclusively nasal breathing) and wakefulness. When awake, the subjects were either seated (with the head neutral, flexed, extended, or rotated) or recumbent (dorsal and lateral positions). MAIN OUTCOME MEASURES: Comparison of pressures within the group as a function of body position and between the groups as a function of snoring. RESULTS: Differential nasal and pharyngeal pressures were similar in seated snorers and nonsnorers independently of head position. Assumption of recumbency resulted in significantly increased pharyngeal pressures in nonsnorers (26 +/- 18 Pa seated vs. 52 +/- 46 Pa recumbent, p < .05) and snorers (50 +/- 35 Pa seated vs. 93 +/- 38 recumbent, p < .01). The increase was higher in snorers than nonsnorers. During snoring, sleep differential pharyngeal pressures in snorers were markedly increased compared to quiet sleep (567 +/- 450 Pa during snoring epochs vs. 117 +/- 82 Pa during nonsnoring epochs, p < .01). CONCLUSIONS: Compared to nonsnorers, recumbent nonapneic snorers have elevated differential pharyngeal pressures indicative of increased upper airway resistance and reduced airway patency; this is present during wakefulness and sleep.

Unilateral nasal nitric oxide measurement after nasal surgery.

This study was designed to validate and standardize a method for unilateral nasal nitric oxide (NO) measurement. Fourteen healthy volunteers and 11 patients who had undergone unilateral medial maxillectomy were enrolled. Nasal NO was measured unilaterally by means of a dual pump system, and bilateral nasal NO was measured by aspirating air through the nasal airway in series. The median unilateral NO output was 195 nL/min on the surgical side and 291 nL/min on the contralateral, surgically untreated side (p = .006). The NO output was not significantly different between nostrils in the control group (p = .82). With the bilateral technique, there was no significant difference between the surgery group and the healthy-subjects group (p = .72). The unilateral nasal NO technique is sensitive in determining unilateral differences in nasal NO production. The NO outputs from the nostrils were similar in normal subjects regardless of the nasal cycle, but were significantly lower on the operated side in the unilateral nasal surgery group.

Nasal nitric oxide is not altered by topical anesthesia.

This prospective study was undertaken to determine whether topical nasal anesthetic agents affect nasal nitric oxide (NO) output in healthy adults. Seven volunteers (aged: 29-56 (40.6 +/- 10.7) years, six male), were recruited. A topical anesthetic (4% lidocaine or 0.5% tetracaine) was sprayed into the subject's right nostril while the left nostril served as a control. Unilateral nasal NO and nasal volume were measured before administration of the anesthetic and at 15 and 30 minutes after the administration. The mean (+/- SD) unilateral nasal NO output was 307 +/- 45.9 nL/minute from the right nostril (exposure side) before the topical application of lidocaine. At 30 minutes after topical application (n = 6), it was 295.5 +/- 41.5 in the right nostril and 297.5 +/- 39.8 in the left (control side). In the tetracaine group (n = 7), the mean (+/- SD) unilateral nasal NO output was 302 +/- 53.3 before the administration and 307 +/- 39.7 at 30 minutes after the administration in the right nostril. The mean NO output in the left nostril at 30 minutes after the administration was 297.7 +/- 40.75. In neither group was there any significant difference in nasal NO output between either the pre- and postlocal anesthetic application on the exposure side (Group 1, P = 0.76; group 2, P = 0.41) or the two nostrils after topical anesthesia application (group 1, P = 0.83; group 2, P = 0.62). Topical anesthesia with either lidocaine or tetracaine does not alter nasal NO output. NO measurement should not be affected in circumstances that require topical anesthesia of the nasal cavity.

Hypoxia depresses nitric oxide output in the human nasal airways.

OBJECTIVES: The role of oxygen in the nasal air on nasal nitric oxide (NO) output was studied in 13 adult volunteers. METHODS: Nasal NO was measured while air containing oxygen (0%-100% in nitrogen) was aspirated through the nasal airway before and after the topical application of xylometazoline. RESULTS: The mean nasal NO output of the untreated nose was 507.8 +/- 161.9 nL/min (mean +/- SD) when 21% oxygen was aspirated through the nasal cavities in series and remained unaltered by 100% O2 (P = .79). Below 10% oxygen the reduction in nasal NO output correlated positively and significantly with the decrease in oxygen concentration (r2 = 0.14). NO output was 245.2 +/- 153.4 nL/min at 0% oxygen, a significant decline from 21% oxygen (P < .0001). Nasal vasoconstriction induced by xylometazoline and alterations in the blood oxygen content by a maximal breath-holding or breathing 100% oxygen did not alter nasal NO in hypoxia (P = .41). CONCLUSIONS: Nasal NO output is markedly depressed in hypoxia and is oxygen dependent at concentrations of less than 10%. Approximately 50% of nasally generated NO is produced from oxygen in nasal air or regulated by it.

[Nitric oxide in the nose and paranasal sinuses--respiratory tract physiology in a new perspective]. / Nitrogenmonoksid i nese og bihuler--luftveienes fysiologi i et nytt perspektiv.

Nitric oxide (NO) has important functions in a variety of physiological and pathophysiological processes in the body, including vasoregulation, haemostasis, neurotransmission, immunity and respiration. The discovery of surprisingly high concentrations of NO in the nasal airway and paranasal sinuses has important implications for the understanding of airway physiology. The high NO levels in the nasal and paranasal airways contribute to the first line defence against microorganisms. Furthermore, autoinhalation of nasal NO may improve pulmonary function and other remote physiological processes. This airborne messenger system represents a new physiological concept of potential clinical importance. However, NO, like several other mediators, has a dualistic function. Airway NO levels are increased in airway inflammations, such as asthma and allergic rhinitis, but is reduced in cystic fibrosis and other conditions with ciliary dysfunction, sinusitis and after exposure to tobacco and alcohol. Consequently, NO may prove valuable as a non-invasive marker in the diagnosis and monitoring of airway pathologies.

Does nasal nitric oxide come from the sinuses?

OBJECTIVE: The purpose of this study was to assess nitric oxide (NO) output by the nose and sinuses. METHOD: In one volunteer, the osteomeatal complex and sphenoethmoidal recess were occluded to isolate the nose from the sinuses. The antrum and frontal sinus were each punctured by two catheters and irrigated with air at constant flow. Nitric oxide output and its rate of accumulation in the absence of air flow were measured in each sinus and in the adjacent nasal cavity. RESULTS: Prior to ostial occlusion, NO output in the nose was 96 nL/min. It decreased by 12% after blockage of all of the ostia. In the isolated sinuses, it was 190 nL/min (antrum) and 68 nL/min (frontal). After 5 minutes stagnation; NO concentration [NO] rose in the occluded sinuses to 24,700 nL/L in the antrum and 22,300 nL/L in the frontal sinus. In the nose, it increased to 29,000 nL/L. When the period of stagnation was prolonged in the frontal sinus, the [NO] reached a plateau. NO output and accumulation were not altered in the nose or either sinus by opening their ostia. In the antrum and frontal sinus, lidocaine reduced NO output and the rate of NO accumulation, but not in the nose. CONCLUSIONS: In this volunteer, 88% of nasal NO was derived from the nose itself. Nitric oxide exchange between the frontal sinus, antrum, and nose was negligible. In the absence of air flow, [NO] rose to a plateau in the nose and frontal sinus. Lidocaine inhibited NO output in the sinuses but not the nose.

Aerodynamic influences on nasal nitric oxide output measurements.

Nitric oxide (NO) concentration in aspirated nasal air is flow-dependent. Nasal NO outputs calculated from steady-state plateaux at flows < 1 l/min are substantially smaller than those at flows > 2 l/min. This study aimed to determine the differences in NO output as calculated from the NO concentration plateaux in aspirated nasal air, resulting from different aspiration flows. Nasal NO was determined by chemiluminescent analysis of air obtained from the nasal passages in series during velopharyngeal closure in 8 healthy adults (flows: 0.2-3.7 l/min) and 5 with symptomatic allergic rhinitis (flows: 0.2-3.7 l/min). Mean NO output in the healthy subjects was stable at approximately 315 nl/l/min at flows of 0.2-0.7 l/min, and increased to a second steady output level of approximately 400 nl/l/min (+28%, p < 0.0001) at more physiological flow rates of 2.7 l/min and higher. The symptomatic subjects had substantially higher NO output at all flows (p < 0.001) (709.3 nl/min at 3.7 l/min) than the non-allergic subjects. The flow dependency of the nasal NO output may be explained by failure at low flows for the air stream to penetrate the peripheral parts of the complex nasal passages, and by the presence of a laminar flow regime in which a marginal lamina would tend to insulate the main stream from the mucosa. Thus, previously reported NO outputs obtained at low flows may underestimate nasal NO output compared to output at higher and more physiological transnasal airflow rates, thus affecting interpretation of results.

Aspiration flow optimized for nasal nitric oxide measurement.

The aim of the present study was to evaluate some of the factors which may influence the reliability of nasal NO measurements, and to optimize methods suitable for children and adults. Nasal nitric oxide (NO) output was determined by chemiluminescent analysis of aspirated samples in 16 adults and 6 children. With the velopharyngeal aperture closed, stable NO levels were obtained at flows ranging form 0.9 to 6.2 L/min. NO output averaged 401.0 +/- 145.4 nL/min./M2 in 6 children, 338.2 +/- 92.3 in 7 adult females and 268.6 +/- 70.2 in 9 adult males. Nasal NO output was independent of flow provided a stable plateau of NO value was reached. In this study, the optimal range of flows was 3.2-5.2 L/min. in adults and 2.2-3.2 L/min. in children. This enables selection of the most favorable flow to be chosen for individual subjects and situations.

Nasal nitric oxide is independent of nasal cavity volume.

This study was performed to evaluate the relationship between nasal nitric oxide (NO) and changes in nasal cavity volume resulting from the topical application of xylometazoline and saline and between upright and supine posture. Nasal NO was measured using a fixed high flow technique that avoids contamination with lower airways NO. In nine healthy subjects nasal NO concentration was measured by a rapid response chemiluminescent analyzer. A tapered tube was inserted in one nostril, into which room air was insufflated to produce a constant flow of 100 mL/second; another tube was inserted into the opposite nostril for NO sampling (air exit side). Subjects were instructed to keep the vellum closed while NO was sampled through a sideport connected to the analyzer. Nasal cavity volume was measured by acoustic rhinometry from a segment of the acoustic pathway, 2 to 5 cm from the nostril. Nasal cavity volume and NO measurements were made at baseline, 15 minutes, and 60 minutes after intervention (administration of saline 0.9%, xylometazoline or posture changes on 3 consecutive days). Xylometazoline produced a significant increase in nasal cavity volume, together with a significant reduction in NO level at 15 and 60 minutes after intervention. In addition, the change from seated to supine position decreased the total nasal volume significantly, but without changes in nasal NO. No correlation was found between the magnitudes of changes in nasal NO and the changes in nasal volume. Topical application of xylomethazoline resulted in increased nasal cavity volume and reduced NO output. In contrast to previous published reports, a technique using high flow rate insufflation demonstrated an abscence of correlation between the magnitudes of changes in nasal NO and nasal cavity volume brought about by decongestant, saline, or posture.

Comparison of direct and indirect measurements of respiratory airflow: implications for hypopneas.

The purpose of this study was to compare indirect methods for measuring respiratory airflow, such as temperature difference between inspired and expired air, thoracoabdominal movements, and nasal respiratory-airflow pressures-with a more direct measurement of minute ventilation using a head-out body plethysmograph. Measurements were obtained in healthy, awake, seated subjects during sequences of different levels of voluntary hypoventilations at 20 breaths/minute and analyzed to determine how well different methods could identify hypopneas (defined as reduction in minute ventilation by 50% or more). The results varied widely between different methods. Sensitivities ranged from 0 to 1, specificity ranged from 0.33 to 1, positive predictive values (PPV) ranged from 0 to 0.73, negative predictive values (NPV) ranged from 0.68 to 0.93. Cohen's kappa varied between 0 and 0.65 The poorest agreement was for the thermistor method, and the best agreement was obtained when a combination of thoraco-abdominal movements and nasal respiratory-airflow pressure was employed (sensitivity = 0.86, specificity = 0.83, PPV = 0.71, NPV = 0.92, Cohen's kappa = 0.65). We conclude that none of the indirect methods investigated, individually or in combination, proved adequate for identification of voluntary hypopneas in awake individuals.

Nasal resistance in recumbency and sleep.

Nasal resistances to respiratory airflow were measured by computer-assisted rhinomanometry in 21 adult males without major clinical nasal pathology. Measurements were obtained when seated and repeated on assumption of recumbency and during sleep. Resistance in Pa/cm3/s of subjects (n = 21) increased from a mean (+/- SD) of 0.14 +/- 0.07 in seated posture to 0.35 +/- 0.32 in recumbency. In the majority of subjects the increase was modest and was unaffected by sleep. It is suggested that unrecognized mucosal abnormality with resulting impairment of vascular tone or minor structural deviation of the nasal septum could account for the few cases of marked elevation of nasal resistance we observed in recumbency.

A comparison between two methods of measuring pressure in the pharyngeal airway: transducer probe versus open catheter.

A new multi-transducer probe system for measuring pharyngeal pressures was compared with an established open catheter system. Pharyngeal pressure measurements were made at the same time, and site, in subjects awake, at unmodified and with artificially increased nasal airway resistances, and during sleep documented by polysomnography. The two systems yielded almost identical results. It is anticipated that the multi-transducer probe system will prove of clinical value.

Diagnostic airway pressure recording in sleep apnea syndrome.

A comparison was made between polysomnographic recordings and recordings of airflow pressures in the pharynx and respiratory pressures in the esophagus of 10 adult sleeping subjects with differing degrees of apnea. Pressure measurements were obtained by microsensors mounted on a 7F gauge flexible catheter which sited them in the epi-, meso- and hypopharynx and the esophagus. Digitized overnight pressure data were stored on a PC memory card and subsequently displayed for analysis by means of a notebook computer. In 2 patients examination of 200 obstructive, mixed and central apneic events showed no significant differences in recordings of their incidence, duration of classification between polysomnographic and either pharyngeal or esophageal pressure techniques. Onset of apnea was demonstrated with particular clarity by computer integration of the pressure tracings. The multiple pressure sensor method offered a further important advantage in detecting the caudal limits of pharyngeal obstructions by steep elevation of the pressure gradient in the pharyngeal segment between adjacent sensors in which the caudal limit of the obstruction was sited. The multiple pressure sensor technique provided reliable and comprehensive diagnostic information of breathing disorders in sleeping subjects and together with its miniaturized recording equipment the method commends itself as suitable for home monitoring.

Pharyngeal airflow during sleep.

This study was conducted to investigate the effects of sleep and nasal resistance on pharyngeal airflow in a group of healthy male adults without complaint of habitual snoring. Twelve subjects aged 21 to 60 years were studied in a sleep laboratory during exclusive nasal breathing. Nasal and pharyngeal airflow variables were measured concomitantly at different stages of sleep. Awake pharyngeal resistance averaged 0.02-0.03 Pa/cm3/s in recumbency. In stage 2 sleep and quiet breathing resistance increased by a factor of 3-4 and by a factor of 7-8 during snoring. Increased nasal loading did not increase pharyngeal resistance further or induce snoring. Mostly, increased pharyngeal resistances were of similar magnitude in both phases of respiration, but in a few instances inspiratory resistance exceeded that in expiration, and in a similar number the reverse was found. Overall, compliance of the pharyngeal airway was not a prominent feature in this group of subjects. The relationship between transpharyngeal pressure and resistance should be studied further in order to simplify future studies of airflow during sleep.

Subjective and objective assessment of uvulopalatopharyngoplasty for treatment of snoring and obstructive sleep apnea.

This study was designed to assess the subjective and objective effects of uvulopalatopharyngoplasty (UPPP) for treatment of snoring. We mailed a questionnaire dealing with snoring, quality of sleep, and interference with bed-partner's sleep to 100 unselected patients who were referred because of snoring. Replies were received from 69 patients. The answers were analyzed, and the subjective impressions were compared with preoperative and postoperative objective measurements of snoring and apnea. The average (+/- SD) length of follow-up was 45 +/- 20 mo. We found no significant differences in the apnea/hypopnea index, snoring index, and mean and maximal nocturnal sound intensity before and after surgery in this group. However, despite this lack of objective improvement. 78% of patients reported reduction in snoring, and 79% reported improvement in the quality of sleep; 18 of 69 bed partners no longer complained of interference with their sleep compared with only one preoperatively. We conclude that if the purpose of UPPP is to reduce the reported health hazards associated with snoring, then comparison between objective preoperative and postoperative measurements of snoring does not indicate success; if, on the other hand, the purpose of surgery is to alleviate the social hazard, then UPPP partially achieves this goal.

Sleep and posture.

Computer-assisted open catheter studies of 10 healthy, nose-breathing men in dorsal and in lateral recumbent sleep demonstrated stable intrasubject transpharyngeal differential pressures and airflow resistances. They averaged 19.6 Pa (+/- standard deviation [SD] 11.9) and 0.103 Pa/cm3 per second (+/- SD 0.065) in the dorsal posture and stage II sleep during quiet breathing and were not significantly different in the lateral posture or in stage I sleep. Five subjects were snorers, and their pharyngeal airflow pressures and resistances increased substantially during quiet breathing on assumption of recumbency and much more in sleep. In the 5 subjects who were nonsnorers, postural changes were not significant and sleep increases were moderate. During snoring, transpharyngeal pressures and resistances increased even further, averaging 188 Pa and 1.02 Pa/cm3 per second for the whole group. Transpharyngeal differential pressures and hypopharyngeal transmural pressures frequently exceeded 300 Pa in inspiration and in expiration during periods of snoring. Yet, transpharyngeal differential pressures and resistances did not reveal appreciable differences between phases that would indicate compliant change of pharyngeal cross section. Breathing frequency was unchanged, but ventilation was significantly diminished at elevated upper airway resistances (P < .01). Transpharyngeal resistances and differential pressures varied independently from widely differing nasal resistances. As with our earlier studies, pressure measurements alone clearly demonstrated breathing patterns and events.