Protocol therapy for acute asthma: therapeutic benefits and cost savings.

BACKGROUND: To evaluate the therapeutic and financial benefits of protocol therapy for acute asthma using standard medications. MATERIALS AND METHODS: This study employed a sequential design in which the influence of an asthma care path on hospital admissions, length of stay (LOS) in the emergency department, and return visits were evaluated for 1 year. This information was contrasted with similar data obtained from the 8 months immediately before the protocol was implemented (preprotocol) and a 12-month period after strict adherence to it had declined (admixture). RESULTS: In all, 526 acute exacerbations of asthma were treated with the care path, and 429 and 558 episodes were evaluated during the preprotocol and admixture periods, respectively. There were no significant differences between the presenting clinical or physiologic features of any group. With the protocol, 77% of the patients resolved their symptoms within 1:47 +/- 0.02 hours:minutes of arrival in the emergency department with a 2% return rate within 24 hours. The algorithms used quickly identified those needing hospitalization. Patients not meeting the criteria for discharge after receiving the treatments employed typically did not resolve their symptoms for days (average hospital stay 4.1 +/- 0.2 days). Compared with the preprotocol period, the care path significantly reduced the LOS by 50 minutes, the number of urgent and intensive care unit admissions by 27% and 41%, respectively, and the frequency of return visits within 24 hours by 66%. Charges to patients and third-party payors decreased $395,000. When adherence to the protocol diminished, LOS, admissions, and returns rose significantly toward preprotocol values and the financial benefits were lost. CONCLUSIONS: Asthma protocol therapy, based primarily upon aggressive use of sympathomimetics in association with serial monitoring of key indices of improvement, provides prompt and efficient relief for acute exacerbations of asthma. Such an approach yields significant financial benefit while quickly identifying individuals who require hospitalization, and it also detects physician practice patterns that can have potentially detrimental impacts on patient care.

Central effects of somatostatin and atrial natriuretic peptide on tracheal tone.

The effects of somatostatin and atrial natriuretic peptide applied topically to the ventral surface of the medulla (VMS) on tracheal tone and phrenic nerve activity (Phr) were studied in chloralose-anesthetized and paralyzed cats artificially ventilated with 7% CO2 in O2. Surface application of drugs to the chemosensitive areas of the VMS significantly decreased tracheal tension measured by changes in pressure in a balloon placed in a bypassed segment of the trachea (Ptseg). Application of somatostatin (9 cats) caused a mean decrease in Ptseg from 17.3 +/- 1.8 (SE) to 4.3 +/- 1.4 cmH2O (P < 0.01) and a reduction in Phr from 24.9 +/- 3.4 to 10.3 +/- 3.4 units (P < 0.05). Like somatostatin, application of atrial natriuretic peptide to the VMS (5 cats) produced tracheal relaxation (Ptseg decreased from 19.3 +/- 2.6 to 9.9 +/- 1.3 cmH2O, P < 0.01), but in contrast there was an insignificant reduction in Phr (from 18.5 +/- 3.6 to 16.1 +/- 3.8 units, P > 0.05). When parasympathetic activity was abolished by atropine methylnitrate and tracheal tone was restored with 5-hydroxytryptamine, somatostatin and atrial natriuretic peptide applied on the VMS had no effect on tracheal pressure, suggesting that observed changes were not caused by direct action of peptides on tracheal smooth muscle via the bloodstream or by facilitation of inhibitory pathways. Both somatostatin and atrial natriuretic peptide applications were associated with a slight but significant decrease in arterial blood pressure. These data suggest that somatostatin and atrial natriuretic peptide acting on the chemosensitive structure of the VMS may play significant roles in modulating para-sympathetic outflow to airway smooth muscle.

Effect of dantrolene on ventilation and respiratory muscle activity in anaesthetized dogs.

The effect of dantrolene on ventilation and ventilatory muscle activity was evaluated in spontaneously breathing anaesthetized dogs. When administered as a bolus of 1.5 mg kg-1 i.v., dantrolene caused hypercapnia. Under isocapnic conditions, with end-tidal PCO2 maintained at 8.1 (SEM 0.3) kPa by adjusting inspired carbon dioxide, dantrolene decreased tidal volume from 475 (66) to 254 (46) ml and breathing rate from 21 (4) to 15 (3) b.p.m. (P less than 0.01 for both). Occlusion pressure was reduced, but the rate of rise of the diaphragm and intercostal EMG were unchanged and peak activity increased only as a result of prolongation of inspiration. Respiratory variables returned gradually to baseline values 1 h after dantrolene administration. Phrenic nerve stimulation revealed a marked reduction in the ability of the diaphragm to generate pressure, particularly at low frequencies of stimulation. Only partial recovery was observed after 1 h. It is concluded that dantrolene causes hypoventilation in the anaesthetized dog when given in large doses i.v.

Central modulatory effects of tachykinin peptides on airway tone.

Previous studies suggest that structures within 1 mm of the ventral surface of the medulla (VMS) are involved in the regulation of airway resistance. Furthermore, neurons containing tachykinin peptides have been observed near the surface of the VMS. In the present work, we examined the effects of mammalian tachykinins, substance P (SP) and neurokinin A (NKA), applied locally to the intermediate area of the VMS of cats on tracheal tone and phrenic nerve activity. Since neutral endopeptidase (enkephalinase) has been shown to degrade tachykinin peptides in other tissues, we also investigated the effect of the neutral endopeptidase (NEP) inhibitors (thiorphan and phosphoramidon) on airway tone and phrenic nerve responses to tachykinins when the animals were ventilated with 100% O2 and during hyperoxic hypercapnia and isocapnic hypoxia. Experiments were performed in chloralose-anesthetized cats hyperventilated to phrenic neural apnea or so that the end tidal CO2 was just above the apneic threshold. Trachealis smooth muscle tension was assessed by measuring changes in pressure in a balloon placed in a bypassed segment of trachea (Ptseg). Application to the VMS of SP (10(-5)-10(-3) M) significantly increased tracheal muscle tension. Similar effects were found with applications of NKA. In addition, thiorphan and phosphoramidon potentiated the effects of tachykinins and the responses to hypercapnia and hypoxia of tracheal tone and phrenic nerve activity. Pretreatment with atropine (1 mg/kg) blocked tracheal but not phrenic responses to tachykinins. These suggest that (1) tachykinins acting on structures located on the VMS can increase cholinergic outflow to the airways and augment respiratory motor output, and (2) NEP may be one important modulator of tachykinin-induced effects.

Role of the ventral surface of medulla in the generation of Mayer waves.

The regions adjacent to the ventrolateral medullary surface (VMS) play critical roles in the regulation of respiratory and cardiovascular function. Furthermore, these areas seem to be important sites for the integration of afferent inputs from certain sensory organs and the source of excitatory inputs to preganglionic sympathetic and parasympathetic neurons. To determine whether the VMS contributes to the generation of nonrespiratory-related periodic oscillations of arterial blood pressure (Mayer waves), excitatory substances, such as N-methyl-D-aspartate (NMDA), cholinergic agonists, and neuropeptides (substance P, neurokinin A, neurotensin), were applied topically to the intermediate area of VMS in anesthetized cats. In addition, the effects of application of lidocaine and inhibitory substances (benzodiazepines) on Mayer waves were studied. After application of excitatory substances to the VMS, we observed oscillations of arterial blood pressure, recurring with a period of 17.8 +/- 10 (SE) s, which had similar characteristics as the Mayer waves recorded during hypercapnia or hypoxia. In addition, cyclic changes in phrenic nerve activity and tracheal tone occurred with the same periodicity as arterial blood pressure oscillation. Application of lidocaine or benzodiazepines on the intermediate area of the VMS abolished Mayer waves observed during hypercapnia, hypoxia, or application of excitatory substances. These findings show for the first time that the VMS can be considered as one of several synaptic relays involved in the generation of arterial blood pressure oscillation, as well as the cyclic changes in phrenic nerve activity and tracheal smooth muscle tone that occur simultaneously.

Benzodiazepines acting on ventral surface of medulla cause airway dilation.

The benzodiazepines that have anxiolytic, anticonvulsant, muscle-relaxant, and sedative-hypnotic properties affect respiration possibly by acting on gamma-aminobutyric acid (GABA)ergic receptors. This study investigated the effects of benzodiazepines diazepam and midazolam) applied topically to or microinjected just beneath the ventrolateral medullary surface (VMS) on airway tone in alpha-chloralose-anesthetized, paralyzed, and artificially ventilated cats. Trachealis smooth muscle tension was assessed by measuring the changes in pressure in a balloon placed in a bypassed rostral segment of the trachea. In 21 cats ventilated with 7% CO2 in O2, surface application of benzodiazepines caused a significant decrease in tracheal tone. Similar to topical application, microinjection of midazolam (1 microgram) in the ventral medulla (0.1-0.2 mm from the surface) in six cats decreased tracheal pressure by 13.2 +/- 2.1 cmH2O (P less than 0.01). In addition, application of benzodiazepines on the VMS in animals ventilated with 12% O2 in N2 (n = 5) decreased tracheal pressure from 15.9 +/- 2.2 to 5.2 +/- 2.7 cmH2O (P less than 0.05). Furthermore, in all cats studied (n = 6), the magnitude of lung deflation-induced tracheal contraction was reduced after application of benzodiazepines on the ventral surface of the medulla (from 11.4 +/- 1.6 to 2.2 +/- 0.9 cmH2O; P less than 0.01). The effects of benzodiazepines on tracheal tone were reversed and blocked by application of Ro 15-1788, a specific benzodiazepines antagonist. However, when parasympathetic activity was abolished by atropine and tracheal tone was restored with 5-hydroxytryptamine, benzodiazepines applied on the VMS had no effect on tracheal pressure. These results suggest that benzodiazepines acting centrally, on structures located near the VMS, can cause a decrease in airway smooth muscle tone by diminishing the activity of parasympathetic neurons which project to the airways.

Influence of respiratory drive on airway responses to excitation of lung C-fibers.

To determine whether the responses of tracheal smooth muscle and the nasal vasculature to stimulation of lung C-fiber receptors depend on the level of respiratory drive, the effects of right atrial injection of capsaicin and phenyldiguanide were studied in chloralose-anesthetized, paralyzed, artificially ventilated cats. Studies were performed while the animals were hyperventilated to apnea and, in addition, when breathing was stimulated by inhalation of 7% CO2 or by N-methyl-D-aspartic acid (NMDA) applied to the ventral surface of the medulla. When the cats were hyperventilated to apnea with O2, injection of capsaicin into the right atrium increased tracheal tone and slightly raised nasal resistance. However, when the animals were ventilated with 7% CO2 in O2 or respiratory activity was stimulated by the application of NMDA, administration of capsaicin eliminated spontaneous phrenic nerve activity and caused an abrupt decrease in tracheal tone but still increased nasal resistance. Similar responses were also obtained with right atrial injection of phenyldiguanide. These results showed for the first time that in the cat the direction of the reflex effects on tracheal tone but not nasal resistance depends on the preexisting level of respiratory drive and on cholinergic activity to airway smooth muscle.

Role of costal and crural diaphragm and parasternal intercostals during coughing in cats.

The inspiratory phase of coughs often consists of large inspired volumes and increased motor discharge to the costal diaphragm. Furthermore, diaphragm electrical activity may persist into the early expiratory portion of coughs. To examine the role of other inspiratory muscles during coughing, electromyograms (EMG) recorded from the crural diaphragm (Dcr) and parasternal intercostal (PSIC) muscles were compared to EMG of the costal diaphragm (Dco) in anesthetized cats. Tracheal or laryngeal stimulation typically produced a series of coughs, with variable increases in peak inspiratory EMGs of all three muscles. On average, peak inspiratory EMG of Dco increased to 346 +/- 60% of control (P less than 0.001), Dcr to 514 +/- 82% of control (P less than 0.0002), and PSIC to 574 +/- 61% of control (P less than 0.0005). Augmentations of Dcr and PSIC EMG were both significantly greater than of Dco EMG (P less than 0.05 and P less than 0.002, respectively). In most animals, EMG of Dco correlated significantly with EMG of Dcr and of PSIC during different size coughs. Electrical activity of all three muscles persisted into the expiratory portions of many (but not all) coughs. The duration of expiratory activity lasted on average 0.17 +/- 0.03 s for Dco, 0.25 +/- 0.06 s for Dcr, and 0.31 +/- 0.09 s for PSIC. These results suggest that multiple respiratory muscles are recruited during inspiration of coughs, and that the persistence of electrical activity into expiration of coughs is not unique to the costal diaphragm.

Tracheal and phrenic responses to neurotensin applied to ventral medulla.

Respiratory activity and airway tone can be significantly affected by perturbations confined to superficial areas of the ventrolateral surface of the medulla (VMS). It is not clear which neuromediators are responsible for these changes. Neurotensin (NT), a tridecapeptide, fulfills many of the criteria required for a neurotransmitter or a neuromodulator. In this study, we determined whether NT applied topically to the intermediocaudal area of VMS could alter tracheal tone (Ptseg) and phrenic nerve activity (Ph) in alpha-chloralose-anesthetized cats hyperventilated with O2 to neural apnea. Also, the effects of NT on the responses of tracheal tone and phrenic nerve activity to steady-state hyperoxic hypercapnia (3% CO2 in O2) and isocapnic hypoxia (12% O2) were tested. Application of pledgets containing NT (10(-5)-10(-3) M) caused significant increases in Ptseg and Ph activity without significant changes in blood pressure. Both tracheal and phrenic responses to hypercapnia and hypoxia were also increased by an earlier application of NT. Application of lidocaine (2%) to the VMS rapidly reversed NT-induced responses and prevented them on reapplication of NT. Phosphoramidon, a neutral endopeptidase inhibitor, potentiated responses to NT, suggesting that a mechanism exists at the VMS that could reverse NT effects. Earlier topical administration of hexamethonium bromide to the VMS did not influence the effects of NT, indicating that NT was not acting by causing the release of acetylcholine. Intravenous administration of atropine (1 mg/kg) blocked tracheal but not phrenic responses to NT. These findings suggest that neurotensin may be a neuromodulator involved in central chemosensitivity and that it may participate in the regulation of phrenic activity and parasympathetic tone of airway smooth muscle.

Effect of stimulation of pulmonary C-fiber receptors on canine respiratory muscles.

The effects of stimulation of pulmonary C-fiber receptors on the distribution of motor activity to upper airway, rib cage, and abdominal muscles were studied in anesthetized, tracheotomized, spontaneously breathing dogs. Stimulation of pulmonary C-fiber receptors by injection of capsaicin (3-20 micrograms/kg) into the right atrium resulted in complete cessation of electrical activity of the upper airway dilating muscles (UADM) and the inspiratory chest wall pumping muscles. The activity of abdominal muscles was also inhibited. The duration of electrical silence was longer for the diaphragm than for the UADM. Upper airway constricting muscles and expiratory intercostal muscles, including the triangularis sterni, remained tonically active during the apneic period. The responses of these muscles were qualitatively the same when the animals breathed 100% O2, 7% CO2 in O2, or 12% O2 in N2, and without or in the presence of an expiratory threshold load. Bilateral vagotomy abolished the inhibitory effects of capsaicin on UADM, chest wall, and abdominal muscle activity, suggesting that the vagus is the major afferent pathway for the reflex. The qualitative difference in the response of intercostal expiratory muscles and abdominal muscles suggests that these two groups of synergistic muscles may be independently regulated.

Nasal and tracheal responses to chemical and somatic afferent stimulation in anesthetized cats.

Respiratory chemical and reflex interventions have been shown to affect nasal resistance or tracheal tone, respectively. In the present study, nasal caliber (assessed from pressure at a constant flow) and tracheal tone (assessed from pressure in a fluid-filled balloon within an isolated tracheal segment) were monitored simultaneously in anesthetized, paralyzed, artificially ventilated (inspired O2 fraction = 100%) cats. We examined the effect of CO2 inhalation and sciatic nerve stimulation as well as the application of nicotine (6 X 10(-4) mol/l) or lidocaine (2% solution) to the intermediate area of the ventral medullary surface (VMS). CO2 and VMS nicotine resulted in a significant increase in tracheal pressure [147 +/- 73 and 91 +/- 86% (SD), respectively]; and a significant reduction in nasal pressure (-35 +/- 10 and -20 +/- 13%, respectively). In contrast, sciatic nerve stimulation resulted in a significant fall in both tracheal (-50 +/- 36%) and nasal pressure (-21 +/- 13%). Application of 2 or 4% lidocaine to the VMS reduced tracheal pressure but did not significantly affect nasal pressure. After VMS lidocaine, nasal and tracheal responses to CO2, sciatic nerve stimulation, or VMS nicotine, when present, were negligible. These results suggest a role for the VMS in the regulation and coordination of nasal and tracheal caliber responses.

Cooling the intermediate area of the ventral medullary surface affects tracheal responses to hypoxia.

The intermediate area of the ventral medullary surface (VMS) influences changes in airway tone caused by hypercapnia and intrapulmonary irritant receptor activation. These studies evaluated the effects of cooling the intermediate area of the VMS on the reflex hypoxic responses of the trachealis smooth muscle and of the phrenic nerve. Anesthetized, paralyzed cats were hyperventilated with 100% oxygen to produce phrenic neural apnea. Tracheal tone was measured indirectly by evaluating pressure changes in an innervated tracheal segment and the phrenic electroneurogram was determined from the central end of a cut cervical root. Switching the inspired gas to 12% O2 increased tracheal pressure of 11 of 12 cats but caused phrenic activity to reappear in only 6 of the animals. Ventilation with 6% O2 significantly increased tracheal constriction prior to phrenic activity. After intravenous administration of atropine methyl nitrate tracheal responses to hypoxia were abolished but phrenic neural responses were unaltered. Neither the tracheal pressure nor the phasic phrenic electroneurogram responded to hypoxia after cutting the carotid sinus nerves. When the intermediate area of the VMS was cooled to 20 degrees C prior to ventilation with the hypoxic gases, both tracheal and phrenic responses were significantly diminished. While the cats were hyperventilated with 6% O2, cooling of the intermediate area significantly diminished tracheal pressure and phrenic nerve activity and both returned to the same levels after rewarming. Cooling of the intermediate area blunted tracheal and phrenic responses to carotid body stimulation by NaCN. However, the appearance of tracheal constriction prior to the onset of phasic phrenic activity may suggest that increased trachealis tone may occur independent of cyclical respiratory activity.

A role for the ventral surface of the medulla in regulation of nasal resistance.

Nasal resistance is known to be affected by changes in nasal blood volume and hence to depend on sympathetic discharge to nasal blood vessels. Structures located superficially near the ventrolateral surface of the medulla significantly affect respiratory and sympathetic activity and the tone of the trachea. To assess the importance of these structures on nasal patency, we measured transnasal pressure at a constant flow and examined the change in pressure produced by topically applied N-methyl-D-aspartic acid (NMDA). Experiments were performed in chloralose-anesthetized, paralyzed, and artificially ventilated cats. NMDA administered on the intermediate area of the ventral surface of the medulla decreased transnasal pressure and increased phrenic nerve activity. The response to NMDA could be diminished or abolished by application to the ventral medullary surface of the NMDA antagonist 2-amino-5-phosphonovalerate (2-APV) or the local anesthetic lidocaine. Carotid sinus denervation and posthypothalamic decerebration did not alter the nasal and phrenic nerve responses to NMDA; however, cervical sympathetic denervation decreased these responses, both in intact and in bilaterally adrenalectomized animals. Therefore, activation of NMDA receptors on structures near the ventral surface of the medulla increases tone in the nasal vasculature and leads to a response pattern that includes changes in not only phrenic nerve activity and blood pressure but also nasal patency.

Effect of N-methyl-D-aspartate applied to the ventral surface of the medulla on the trachea.

Structures located near the ventral surface of the medulla (VMS) affect both cardiovascular tone and respiratory activity. In addition cooling the intermediate area of the VMS blocks the increases in parasympathetic activity and tracheal tone resulting from ventilation with hypercapnic or hypoxic gas mixtures, or due to stimulation of mechanoreceptors within the lung. Since cooling the surface of the VMS may affect fibers of passage as well as cell bodies, we performed studies in which pledgets containing N-methyl-D-aspartic acid (NMDA), a synthetic excitatory amino acid, were applied to intermediate area of the VMS. The studies were performed in chloralose-anesthetized, artificially ventilated cats. Application of pledgets containing NMDA (10(-7) mol at 10(-3) M) caused increases in tracheal pressure and the onset of phasic phrenic activity, but application of 10(-8) mol at 10(-4) M of NMDA could produce tracheal constriction without the appearance of phasic phrenic activity. Applying to the entire VMS either 2-amino-5-phosphonovalerate (2-APV, 10(-6) M), a specific antagonist to NMDA, or lidocaine (2%), a local anesthetic, 60 s before the application of pledgets containing NMDA, prevented the increase in tracheal tone and phasic phrenic activity. Intravenous administration of atropine methyl nitrate 0.5 mg/kg, a cholinergic antagonist, blocked tracheal responses to local application of pledgets containing NMDA but did not affect the increase in phasic phrenic nerve activity. These findings suggest that when stimulated, neurons near the surface of the VMS in the vicinity of the intermediate area increase the activity of parasympathetic fibers to the airway.

Respiratory changes in thoracic muscle length during bronchoconstriction.

The purpose of the present study was to assess the effects of bronchoconstriction on respiratory changes in length of the costal diaphragm and the parasternal intercostal muscles. Ten dogs were anesthetized with pentobarbital sodium and tracheostomized. Respiratory changes in muscle length were measured using sonomicrometry, and electromyograms were recorded with bipolar fine-wire electrodes. Administration of histamine aerosols increased pulmonary resistance from 6.4 to 14.5 cmH2O X l-1 X s, caused reductions in inspiratory and expiratory times, and decreased tidal volume. The peak and rate of rise of respiratory muscle electromyogram (EMG) activity increased significantly after histamine administration. Despite these increases, bronchoconstriction reduced diaphragm inspiratory shortening in 9 of 10 dogs and reduced intercostal muscle inspiratory shortening in 7 of 10 animals. The decreases in respiratory muscle tidal shortening were less than the reductions in tidal volume. The mean velocity of diaphragm and intercostal muscle inspiratory shortening increased after histamine administration but to a smaller extent than the rate of rise of EMG activity. This resulted in significant reductions in the ratio of respiratory muscle velocity of shortening to the rate of rise of EMG activity after bronchoconstriction for both the costal diaphragm and the parasternal intercostal muscles. Bronchoconstriction changed muscle end-expiratory length in most animals, but for the group of animals this was statistically significant only for the diaphragm. These results suggest that impairments of diaphragm and parasternal intercostal inspiratory shortening occur after bronchoconstriction; the mechanisms involved include an increased load, a shortening of inspiratory time, and for the diaphragm possibly a reduction in resting length.

Effects of bronchoconstriction on respiratory muscle activity during expiration.

The effect of methacholine-induced bronchoconstriction on the electrical activity of respiratory muscles during expiration was studied in 12 anesthetized spontaneously breathing dogs. Before and after aerosols of methacholine, diaphragm, parasternal intercostal, internal intercostal, and external oblique electromyograms were recorded during 100% O2 breathing and CO2 rebreathing. While breathing 100% O2, five dogs showed prolonged electrical activity of the diaphragm and parasternal intercostals in early expiration, postinspiratory inspiratory activity (PIIA). Aerosols of methacholine increased pulmonary resistance, decreased tidal volume, and elevated arterial PCO2. During bronchoconstriction, when PCO2 was varied by CO2 rebreathing, PIIA was shorter at low levels of PCO2, and external oblique and internal intercostal were higher at all levels of PCO2. Vagotomy shortened PIIA in dogs with prolonged PIIA. After vagotomy, methacholine had no effects on PIIA but continued to increase external oblique and internal intercostal activity at all levels of PCO2. These findings indicate that bronchoconstriction influences PIIA through a vagal reflex but augments expiratory activity, at least in part, by extravagal mechanisms.

Influence of the ventral surface of the medulla on tracheal responses to CO2.

These studies investigated the role of the intermediate area of the ventral surface of the medulla (VMS) in the tracheal constriction produced by hypercapnia. Experiments were performed in chloralose-anesthetized, paralyzed, and artificially ventilated cats. Airway responses were assessed from pressure changes in a bypassed segment of the rostral cervical trachea. Hyperoxic hypercapnia increased tracheal pressure and phrenic nerve activity. Intravenous atropine pretreatment or vagotomy abolished the changes in tracheal pressure without affecting phrenic nerve discharge. Rapid cooling of the intermediate area reversed the tracheal constriction produced by hypercapnia. Graded cooling produced a progressive reduction in the changes in maximal tracheal pressure and phrenic nerve discharge responses caused by hypercapnia. Cooling the intermediate area to 20 degrees C significantly elevated the CO2 thresholds of both responses. These findings demonstrate that structures near the intermediate area of the VMS play a role in the neural cholinergic responses of the tracheal segment to CO2. It is possible that neurons or fibers in intermediate area influence the motor nuclei innervating the trachea. Alternatively, airway tone may be linked to respiratory motor activity so that medullary interventions that influence respiratory motor activity also alter bronchomotor tone.

Influence of ventrolateral surface of medulla on reflex tracheal constriction.

To assess the role of structures located superficially near the ventrolateral surface of the medulla on the reflex constriction of tracheal smooth muscle that occurs when airway and pulmonary receptors are stimulated mechanically or chemically, experiments were conducted in alpha-chloralose-anesthetized, paralyzed, and artificially ventilated cats. Pressure changes within a bypassed segment of the trachea were used as an index of alterations smooth muscle tone. The effects of focal cooling of the intermediate areas or topically applied lidocaine on the ventral surface of the medulla on the response of the trachea to mechanical and chemical stimulation of airway receptors were examined. Atropine abolished tracheal constriction induced by mechanical stimulation of the carina or aerosolized histamine, showing that the responses were mediated over vagal pathways. Moderate cooling of the intermediate area (20 degrees C) or local application of lidocaine significantly decreased the tracheal constrictive response to mechanical activation of airway receptors. Furthermore, when the trachea was constricted by histamine, cooling of the intermediate area significantly diminished the increased tracheal tone, whereas rewarming restored tracheal tone to the previous level. These findings suggest that under the conditions of the experiments the ventral surface of the medulla plays an important role in constriction of the trachea by inputs from intrapulmonary receptors and in the modulation of parasympathetic outflow to airway smooth muscle.

Medullary effects of nicotine and GABA on tracheal smooth muscle tone.

Airway tone can be modulated centrally by the brain as well as by peripheral receptors. In part these changes in airway caliber seem to be secondary to changes in respiratory activity. Since structures near the ventrolateral medullary surface (VMS) can produce profound effects on respiration, it seems reasonable to believe that they might also be capable of modifying tracheal tone. In this study we examined the effects of two agents with respect to their action on tracheal tone: nicotine, a respiratory stimulant when applied to the VMS, and gamma aminobutyric acid (GABA), a respiratory depressant when similarly administered. In chloralose anesthetized, paralyzed, artificially ventilated cats, tracheal tone was assessed by measuring pressure changes in a rostral bypassed segment of the trachea, while phrenic nerve activity was examined simultaneously. Nicotine administered on the intermediate area of the VMS both before and after carotid sinus denervation increased phrenic activity and induced constriction of the rostral tracheal segment. The response to nicotine could be blocked by application of a nicotine antagonist, hexamethonium, or prior local administration of lidocaine to the VMS. Activation of GABAergic receptors by application of GABA on the intermediate area of the VMS markedly reduced respiratory activity and nearly abolished the increased tracheal tone produced by inhalation of 7% CO2 in O2. The effects of GABA were eliminated by the prior administration to the VMS of bicuculline, a GABA receptor antagonist. These results indicate that structures located on the ventral surface of the medulla which affect breathing may also play a significant role in the regulation of airway smooth muscle tone.

Comparative effects of theophylline and adenosine on respiratory skeletal and smooth muscle.

This study compared the effects of theophylline and adenosine on the contractile activity of respiratory smooth and skeletal muscles in vitro. Studies were performed on isolated strips of tracheal smooth and diaphragmatic skeletal muscle from 22 Hartley strain guinea pigs. The changes in diaphragm and tracheal smooth muscle tension in response to electrical stimulation and histamine-induced contraction, respectively, were assessed over a range of theophylline and adenosine concentrations (10(-7) to 10(-3) M for each). Theophylline increased diaphragmatic tension and reversed histamine-induced smooth muscle contractions in a dose-dependent fashion. Theophylline, however, decreased tracheal tension at concentrations an order of magnitude lower than those that increased diaphragmatic tension. Adenosine mimicked the effect of theophylline on tracheal muscle but had no effect on the force of diaphragm contraction. Moreover, adenosine failed to alter the theophylline dose-response curve for diaphragmatic tension. This study demonstrates that airway smooth muscle is more sensitive than is respiratory skeletal muscle to the effects of theophylline. Furthermore, these data suggest that the effects of theophylline on diaphragm skeletal muscle are not mediated by adenosine receptor blockade.