N. S. Cherniack

Ventilatory responses to transient hypoxia and hypercapnia in man

Abstract The contribution of the peripheral (arterial) chemoreceptors to the ventilatory response to acute hypoxia and hypercapnia in intact unanesthetized man has been evaluated by methods which assume that ventilatory responses to transient stimuli reflect their effects upon the arterial chemoreceptors while responses to steady-state stimuli reflect their effects upon both arterial chemoreceptors and the central nervous system. Transient eucapneic hypoxia was produced by inhalation of several breaths of N 2 while breathing room air; transient hypercapneic hypoxia was produced by inhalation of several breaths of N 2 with CO 2 added while breathing CO 2 enriched air. Transient euoxic hypercapnia was produced by inhalation of single breaths of from 6 to 20% CO 2 in 21 % O 2 while the subject breathed air; transient hypoxic hypercapnia was produced by inhalation of single breaths of CO 2 enriched hypoxic gas while the subjects breathed a similarly hypoxic gas mixture. The ventilatory responses to transient hypoxia were qualitatively similar to the responses to steady-state hypoxia although they were quantitatively significantly greater by an average of 18%. The responses to transient euoxic hypercapnia averaged approximately one-third the responses to steady-state euoxic hypercapnia. Responses to transient hypercapnia were much less enhanced by hypoxia than were responses to steady-state hypercapnia. The findings suggest that: (1) A slight. centrally mediated, depressant effect of hypoxia may be present in unanesthetized man; (2) The peripheral chemoreceptors are responsible for approximately one-third of the overall (steady-state) ventilatory response to hypercapnia; (3) The phenomenon of stimulus interaction (enhancement of ventilatory response to hypercapnia by hypoxia) occurs at both the peripheral chemoreceptors and within the central nervous system but the central effect is the predominant one.

Effects of hypercapnia and inspiratory flow-resistive loading on respiratory activity in chronic airways obstruction.

The respiratory responses to hypercapnia alone and to hypercapnia and flow-resistive loading during inspiration were studied in normal individuals and in eucapnic and hypercapnic patients with chronic airways obstruction. Responses were assessed in terms of minute ventilation and occlusion pressure (mouth pressure during airway occlusion 100 ms after the onset of inspiration). Ventilatory responses to CO2 (deltaV/deltaPCO2) were distinctly subnormal in both groups of patients with airways obstruction. The two groups of patients, however, showed different occlusion pressure responses to CO2 (deltaP100/deltaPCO2): deltaP100/deltaPCO2 was normal in the eucapnic patients but subnormal in the hypercapnic patients. Flow-resistive loading during inspiration reduced deltaV/deltaPCO2 both in normal subjects and in patients with airways obstruction. The occlusion pressure response to CO2 increased in normal subjects during flow-resistive loading but remained unchanged in both groups of patients with chronic airways obstruction. These results indicate that while chemosensitivity as determined by deltaP100/deltaPCO2 is impaired only in hypercapnic patients with chronic airways obstruction, an acute increase in flow resistance elicits a subnormal increase in respiratory efferent activity in both eucapnic and hypercapnic patients.

Hypoxia and hypercapnia as respiratory stimulants and depressants.

Abstract The effect of wide variations in arterial O2 and CO2 tensions on phrenic nerve activity was evaluated in anesthetized dogs which were paralyzed so that the physical properties of the lung and chest wall could not influence respiratory neuron response. The techniques used allowed the effects of hypoxia and hypercapnia to be assessed either separately or in combination. The results showed that hypoxia enhanced the stimulating effects of hypercapnia on respiratory neuron response by (1) decreasing the arterial CO2 tension at which phasic phrenic activity begins and by (2) increasing the change in phrenic nerve activity produced by a given rise in arterial CO2 tension. However, hypoxia also augmented the depressing effect of hypercapnia by (1) decreasing the arterial CO2 tension at which peak phrenic nerve activity occurred and by (2) reducing the range of arterial CO2 tensions over which progressive hypercapnia increased phrenic nerve activity. The results suggest that the usual steady state methods of evaluating hypoxic response may be measuring opposing effects of hypoxia on ventilation; a stimulating effect of hypoxia at the peripheral chemoreceptor; and a depressing central effect of hypoxia.

The effects of abnormal sympathetic nervous function upon the ventilatory response to hypoxia

THE VENTILATORY RESPONSE TO HYPOXIA WAS STUDIED IN TWO GROUPS OF SUBJECTS WITH ABNORMAL SYMPATHETIC NERVOUS CONTROL: (a) human subjects with familial dysautonomia (Riley-Day syndrome), and (b) unanesthetized goats treated with an alpha-adrenergic blocking agent (phenoxybenzamine). The ventilatory response to hypoxia was evaluated in two ways: (a) from the slope of the relationship between ventilation and alveolar P(Co2) ([unk]V(E)-P(ACo2) slope) during the rebreathing of hypoxic and hyperoxic gases, and (b) from the change in ventilation produced when hypoxia was abruptly relieved. The ventilatory and circulatory responses of the unanesthetized, phenoxybenzamine-treated goats were qualitatively similar to those of dysautonomic patients. In contrast to the sustained stimulation of ventilation produced by hypoxia in normal subjects, hypoxia either did not change, or decreased, the [unk]V(E)-P(ACo2) slope of dysautonomic patients and phenoxybenzamine-treated goats; CO(2)-free hypoxia produced a fleeting hyperventilation, which was followed by apnea when hypoxia was abruptly relieved. Unlike normal subjects, the dysautonomic patients and phenoxybenzamine-treated goats became hypotensive while hypoxic. The results indicate that peripheral chemoreceptor reflex responses to hypoxia are preserved in subjects in whom sympathetic nervous responses are impaired. However, the central nervous depression of ventilation by hypoxia is enhanced simultaneously. The inordinate central depression is attributed to the inability of the dysautonomic subjects and goats to maintain systemic blood pressure and, consequently, cerebral blood flow during hypoxia, thereby aggrevating central nervous hypoxia.

Comparison of occlusion pressure and ventilatory responses.

The airway pressure 100 msec after the onset of an inspiratory effort against a closed airway (P100, occlusion pressure) is theoretically a more accurate index of respiratory neuron motor output than ventilation. Occlusion pressure and ventilation responses to hypercapnia were compared in repeated trials in 10 normal subjects while in the seated and supine positions. During progressive hypercapnia changes in P100 were also compared to changes in tidal volume and inspiratory airflow. These studies show that occlusion pressure increases linearly with hypercapnia in both sitting and supine subjects. Changing from the seated to the supine position, or vice versa, had no significant effect on either ventilation or occlusion pressure responses to CO2. Correlations between P100 and ventilation or airflow rate were significantly higher than correlations between P100 and tidal volume or breathing frequency. Intermittent random airway occlusion had no effect on either ventilation or pattern of breathing during hypercapnia. Occlusion pressure responses were no less variable than ventilation responses in groups of subjects whether studied seated or supine. However, maintenance of a constant moderate breathing frequency (20 breaths per minute) reduced the interindividual variability in ventilation and occlusion pressure responses to hypercapnia.

Effect of fiberoptic bronchoscopy on respiratory performance in patients with chronic airways obstruction.

Lung volumes, airway resistance, expiratory flow rates, distribution of ventilation, and arterial blood gases were measured before and after fiberoptic bronchoscopy in 13 patients with moderately severe chronic airways obstruction and in 10 healthy non-smoking controls. Arterial blood gases were also monitored serially during the procedure. Arterial oxygen tension (Pao2) fell during fiberoptic bronchoscopy in both patients and controls whereas arterial carbon dioxide tension and pH remained unchanged. Control subjects had no change in lung mechanics after fiberoptic bronchoscopy. However, the patients consistently developed increased airway obstruction after fiberoptic bronchoscopy. Within 24 hours after bronchoscopy lung function in the patients returned to baseline values, except for the residual volume which remained abnormally high. The topical application of lignocaine (Lidocaine) for local anesthesia before fiberoptic bronchoscopy produced no effect on lung mechanics in nine patients and 10 controls, but Pao2 decreased in both the patient and control groups. These results indicate that fiberoptic bronchoscopy consistently inpairs lung mechanics and gas exchange in patients with chronic airways obstruction but that the impairment is mild and reversible. Lignocaine administration as well as the intubation procedure contribute to the fall in Pao2 which occurs both in the patients and in subjects without pre-existing lung disease.

Effects of a molecular change in collagen on lung structure and mechanical function.

Semicarbazide, a lathyrogen, was given to growing rats to elucidate the consequences of altering the molecular structure of fibrous proteins within the lung. Static pressure-volume (P-V) measurements during deflation of saline-filled lungs showed normal recoil pressure and compliance values within the physiological range of lung volume. Quasi-static P-V measurements were also normal during slow reinflation, even beyond physiological limits to a recoil pressure of 20 cm H20. However, the lungs of experimental rats ruptured at much lower recoil pressures than controls. Histology was normal in lungs fixed at 20 cm H20. In contrast, lungs showed dilation of terminal air spaces, rupture of alveolar walls, and an increase in mean linear intercept in experimental compared with control specimens, when fixed at 30 cm H20. Biochemical analyses revealed reduced cross-linking of lung collagen without change in its total content. There were no detectable changes in the quantity or quality of lung elastin. It is concluded that semicarbazide may selectively impair the maturation of lung collagen and that immaturity of lung collagen is associated with a reduction in the tensile strength of lung tissue, without changes in elasticity within physiological volume limits.

Airway occlusion pressures in awake and anesthetized goats.

The pressures generated by the inspiratory muscles as they contract isometrically during airway occlusion seem to be a measure of respiratory neuron efferent activity. The ventilatory and occlusion pressure responses to increasing levels of CO2 were studied in goats, awake and anesthetized, with and without inspiratory flow resistance. Hypercapnia was produced by rebreathing. Randomly, during rebreathing, inspiratory airflow was prevented on single breaths. Ventilation and pressures developed during the first 100, 200, 300 and 400 milliseconds of an inspiratory effort against a complete occlusion increased linearly with CO2 in both awake and anesthetized animals. Anesthesia reduced both the ventilatory and occlusion pressure responses to CO2. Inspiratory resistance increased occlusion pressure responses in awake goats but not in the same animals when anesthetized. Inspiratory airflow resistance seems to augment respiratory efferent activity as reflected in the pressure responses only in conscious goats. Thus the response to an inspiratory resistance seems to depend on the state of consciousness.

Evaluation of breath holding in hypercapnia as a simple clinical test of respiratory chemosensitivity.

Breath holding was used as the basis of a simple test of respiratory chemosensitivity. Breath holding was begun at selected degrees of hypercapnia produced by CO2 rebreathing. In 16 healthy control subjects there was a linear regression of the log of breath-holding time on the PCO2 at the start of breath holding. Breath-holding time (BHT) and the slope of a log BHT/Pco2 plot were closely correlated with the ventilatory response to CO2. In five cases of the idiopathic hypoventilation syndrome, CO2 retention and reduced ventilatory response to CO2 were accompanied by prolonged breath-holding time and the regression of log BHT on Pco2 was abnormally flat. However, in 17 patients with chronic airways obstruction, breath-holding time was never prolonged and the log BHT/Pco2 relationship was normal, even though 13 had a diminished ventilatory response to CO2 and four had chronic CO2 retention. It is concluded that the BHT/Pco2 relationship provides a useful index of respiratory chemosensitivity which is not influenced by airways obstruction. This may be helpful in the detection of impaired chemosensitivity as a cause of CO2 retention even when the ventilation CO2 response is reduced non-specifically by coexisting airways obstruction.

Respiratory responses to changes in airflow resistance in conscious man

The time course and magnitude of adjustments in respiratory activity during the application and following the removal of inspiratory resistive loads were determined in conscious men. Changes in airflow resistance were made periodically during rebreathing of a gas mixture of carbon dioxide and oxygen. Ventilation, the ratio of tidal volume to inspiratory duration and the mouth pressure during airway occlusion, 100 ms after the onset of inspiration were used as measures of inspiratory neuromuscular activity. The occlusion pressure was measured during each breath using an electrically activated solenoid shutter which obstructed the airway for only the first 100 ms of each inspiration. During the second breath following the application of the resistive load, there was an increase in inspiratory output which occurred independently of changes in PCO2 and PO2. Further increases in inspiratory activity during successive loaded breaths, however, were due exclusively to changing chemical drive. The level of inspiratory neuromuscular activity remained elevated for a single breath following removal of the added resistance. Adjustments in respiratory activity were greater the more severe the load. The results suggest that non-chemically mediated respiratory compensation in conscious individuals develops rapidly and is important in maintaining ventilation when breathing is encumbered.