John V. Weil

Hypoxic ventilatory drive in normal man

A technique is described which permits the inscription of the ventilatory response to isocapnic hypoxia in man as a continuous curve relating alveolar oxygen tension and minute ventilation. The adjustment of ventilation to changes in alveolar oxygen tension is complete in 18-23 sec and this is sufficiently rapid to justify the use of a non-steady-state method. Changes in alveolar carbon dioxide tension are prevented by addition of carbon dioxide to the inspired gas. The resulting [unk]V(E)-P(Ao2) curves are hyperbolic such that falling P(Ao2) produces only slight rises in [unk]V(E) until a critical P(Ao2) range of 50-60 mm Hg is reached. With further fall in P(Ao2), [unk]V(E) increases steeply and the slope of the curve approaches infinity at a tension of 30-40 mm Hg. For purposes of quantitation these curves are approximated by a simple hyperbolic function, the parameters of which are evaluated by a least squares fit of the data. The parameter A denotes curve shape such that the higher the value of A. the greater the increase in ventilation for a given decrease in P(Ao2) and hence the greater the hypoxic drive. Curves are highly reproducible for each subject and curves from different subjects are similar. In 10 normal subjects at resting P(ACo2), A = 180.2 +/-14.5 (SEM). When P(ACo2) is adjusted to levels 5 mm Hg above and below control in six subjects A = 453.4 +/-103 and 30.2 +/-6.8 respectively. These latter values differed significantly from control (P < 0.05). These changes in curve shape provide a clear graphic description of interaction between hypercapnic and hypoxic ventilatory stimuli. At normal P(ACo2) the [unk]V(E)-P(Ao2) curve has an inflection zone located over the same P(o2) range as the inflection in the oxygen-hemoglobin dissociation curve. This indicated that ventilation might be a linear function of arterial oxygen saturation or content. Studies in four subjects have demonstrated that ventilation is indeed related to arterial oxygen content in a linear fashion. These data suggest, but do not prove, that oxygen tension in chemoreceptor tissue as in part determined by circulatory oxygen delivery may be an important factor in controlling the ventilatory response to hypoxia.

Respiration during sleep in normal man.

Respiratory volumes and timing have been measured in 19 healthy adults during wakefulness and sleep. Minute ventilation was significantly less (p less than 0.05) in all stages of sleep than when the subject was awake (7.66 +/- 0.34(SEM) 1/min), the level in rapid-eye-movement (REM) sleep (6.46 +/- 0.29 1/min) being significantly lower than in non-REM sleep (7.18 +/- 0.39 1/min). The breathing pattern during all stages of sleep was significantly more rapid and shallow than during wakefulness, tidal volume in REM sleep being reduced to 73% of the level during wakefulness. Mean inspiratory flow rate (VT/Ti), an index of inspiratory drive, was significantly lower in REM sleep than during wakefulness or non-REM sleep. Thus ventilation falls during sleep, the greatest reduction occurring during REM sleep, when there is a parallel reduction in inspiratory drive. Similar changes in ventilation may contribute to the REM-associated hypoxaemia observed in normal subjects and in patients with chronic obstructive pulmonary disease.

Diminished Ventilatory Response to Hypoxia and Hypercapnia after Morphine in Normal Man

Although morphine depresses respiration the mechanism of this depression remains unknown. Accordingly, ventilatory responses to hypoxia and to hypercapnia were measured before and after administration of 7.5 mg of morphine sulfate subcutaneously in six normal subjects. This procedure produced resting hypoventilation manifested as a peak rise in alveolar carbon dioxide tension from 42.9 plus or minus 1.7 to 45.4 plus or minus 1.5 mm Hg (plus or minus S.E.M.) at 30 minutes ( greater than 0.01). Hypoxic ventilatory drive, measured by an index of the relation between ventilation and hypoxia (parameter A), decreased from a control of 108 plus or minus 17.6 to 42.8 plus or minus 5.3 at 60 minutes after morphine (p greater than 0.01); Hypercapnic ventilatory drive, measured as the slope of the ventilatory response to hypercapnia, also decreased from 1.69 plus or minus 0.24 to 0;98 plus or minus 0.20 (p greater than 0.01) 75 minutes after morphine. Decreased responsiveness to the chemical stimuli to breathing may contribute to the ventilatory depression frequently seen after administration of morphine.

Bradycardia during sleep apnea. Characteristics and mechanism.

To determine the characteristics of and mechanisms causing the bradycardia during sleep apnea (SA), both patients with SA and normals were studied. Evaluation of six consecutive SA patients demonstrated that bradycardia occurred during 95% of all apneas (central, obstructive, and mixed) and became marked with increased apnea length (P less than 0.01) and increased oxyhemoglobin desaturation (P less than 0.01). Heart rate slowed 9.5 beats per minute (bpm) during apneas of 10-19 s in duration, 11.4 bpm during 20-39s apneas, and 16.6 bpm during 40-59-s apneas. Sleep stage had no effect unexplained by apnea length or degree of desaturation. Oxygen administration to four SA patients completely prevented the bradycardia although apneas lengthened (P less than 0.05) in three. Sleeping normal subjects did not develop bradycardia during hypoxic hyperpnea but, instead, HR increased with hypoxia in all sleep stages, although the increase in HR was not as great as that which occurred while awake. Breath holding in awake normals did not result in bradycardia during hyperoxia (SaO2 = 99%), but was consistently (P less than 0.01) associated with heart rate slowing during room air breath-holds (-6 bpm) at SaO2 = 93%, with more striking slowing (-20 bpm) during hypoxic breath-holds (P less than 0.01) at SaO2 = 78%. Breath holding during hyperoxic hypercapnia had no significant effect on rate. Breath holding in awake SA subjects demonstrated similar findings. We conclude that the bradycardia of SA is a consistent feature of apnea and results from the combined effect of cessation of breathing plus hypoxemia.

Decreased hypoxic ventilatory drive in the obesity-hypoventilation syndrome☆

Most patients with extreme obesity do not exhibit alveolar hypoventilation, but an intriguing minority do. The mechanism(s) of this phenomenon remain unknown. A disorder in ventilatory control has been suggested as a major factor in the pathogenesis of the obesity-hypoventilation syndrome. Accordingly, hypoxic and hypercapnic ventilatory drives were measured in 10 patients with the typical symptoms of the syndrome: obesity, hypersomnolence, hypercapnia, hypoxemia, polycythemia and cor pulmonale. Hypoxic ventilatory drive, measured as the shape parameter A, averaged 21.9 +/- 5.35, approximately one-sixth that in normal controls, A = 126 +/- 8.6 (P less than 0.01). The ventilatory response to hypercapnia also was markedly reduced, the slope of the response averaging 0.51 +/- 0.005, or about one-third the normal value of 1.83 +/- 0.13 (P less than 0.01). This decreased responsiveness in hypoxic and hypercapnic ventilatory drive was consistent throughout the group. The depression in ventilatory drive found in the obesity-hypoventilation syndrome may be causally related to the alveolar hypoventilation manifested by these patients.

Treatment of Essential Hypertension with a New Vasodilator in Combination with Beta-Adrenergic Blockade

Abstract A new piperidino-pyrimidine vasodilator (PDP) when used in the treatment of 11 hypertensive patients, lowered blood pressure from 188/124 to 159/100 over six to seven days. blood-pressure responses to standing, cold-pressor test and Valsalva maneuver persisted, and postural symptoms did not occur despite marked reduction of blood pressure. However, the antihypertensive action was associated with reflexly induced increases in heart rate, cardiac index and norepinephrine excretion and evidence of myocardial ischemia in some patients. Selective beta-adrenergic blockade with propranolol prevented this augmentation of cardiac activity and further decreased blood pressure. Although glomerular filtration rate and renal plasma flow were unchanged, sodium retention occurred in all patients. Such retention appeared to be readily controllable with oral diuretics in the one patient to whom it was given. Thus, PDP combined with propranolol results in highly effective lowering of blood pressure in hypertensive...

Ventilatory Control in Myxedema and Hypothyroidism

Alveolar hypoventilation is known to occur in myxedema. To clarify the role of hypoxic ventilatory drive and hypercapnic ventilatory drive in thyroid hormone insufficiency states, 10 patients with myxedema and seven with hypothyroidism (thyroid ablation) were studied before and after thyroid replacement. An index developed for hypoxic ventilatory drive was markedly reduced in myxedema: 17 plus or minus 4.7 (S.E.M.) (normal, 126 plus or minus 8.7) (P smaller than 0.01) and increased to 78 plus or minus 12.6 (p = 0.02) with thyroid hormone replacement. In the hypothyroid group this index was also depressed as compared to normal at 67 plus or minus 20 (p smaller than 0.01) and increased to 114 plus or minus 19 (p smaller than 0.02) with replacement. An index for hypercapnic ventilatory drive was depressed in myxedema, 0.69 plus or minus 0.01), but was not significantly depressed in hypothyroidism. With thyroid hormone replacement this index did not significantly increase in either group. We conclude that both myxedema and hypothyroid states produce depression of hypoxic ventilatory drive that is responsive to replacement therapy. This alteration in ventilatory control may contribute to the hypoventilation seen in myxedema.

Clinical semi-starvation: depression of hypoxic ventilatory response.

A decreased metabolic rate has been associated with decreased ventilatory response to hypoxia and hypercapnia, and also with starvation. We fed a 500-calorie carbohydrate diet with supplemental electrolytes, designed to simulate alimentation by usual intravenous fluids, to seven normal subjects for 10 days to determine the effect of semi-starvation on metabolic rate and ventilatory responses. By the 10th day metabolic rate was significantly decreased, and hypoxic ventilatory response decreased to 42% of control (P less than 0.05). In two subjects, hypoxic ventilatory response was virtually abolished at day 10. These changes reversed toward normal with refeeding. The decrease in hypoxic ventilatory response response was significantly (P less than 0.01) related to the decrease in metabolic rate. Hypercapnic ventilatory response, measured as the slope of the ventilatory response to hypercapnia, decreased slightly but not significantly. The decrease in hypoxic ventilatory response seen during semi-starvation may contribute to the hypoxemia and respiratory failure subsequent to caloric restriction.

Acquired attenuation of chemoreceptor function in chronically hypoxic man at high altitude

To determine whether chronic exposure to hypoxia during adulthood produces alterations in the control of ventilation, measurements of the resting ventilatory response to hypoxia and hypercapnia, as well as ventilatory response to hypoxia during exercise, were carried out in a group of 10 long-term (3-39 yr) non-native residents of Leadville, Colo. (elevation 3100 m). A group of 8 subjects native to Leadville was also studied and 10 low altitude subjects of Denver, Colo. (elevation 1600 m) served as controls. Hypoxic ventilatory drive was measured as the shape parameter A of isocapnic VE-PA(o2) curves. In the non-native high altitude resident this parameter averaged 43% of the value for low altitude controls (P<0.05) denoting a diminished ventilatory response to hypoxia. The degree of attenuation was related to the length of time spent at high altitude. In the high altitude natives the parameter A averaged 9.6% of control (P<0.01). Similarly hypercapnic ventilatory drive as measured by the slope of the isoxic VE-PA(co2) lines was reduced in the non-native residents to 65% of control (P<0.05) and in the natives averaged 54% of control (P<0.01). In contrast with these findings at rest induction of hypoxia during exercise produced an increase in ventilation comparable to that in the controls in both groups of highlanders. Hence chronic exposure to hypoxia during adulthood in man results in marked attenuation of the ventilatory response to hypoxia at rest and this is a function of the length of exposure to hypoxia. This attenuation of the ventilatory response to hypoxia was associated with a decrease in hypercapnic ventilatory drive. The fact that hypoxic ventilatory drive was almost completely absent while hypercapnic drive was only partially reduced parallels closely the more important role of the peripheral chemoreceptors in mediating ventilatory responses to hypoxia than to hypercapnia. This suggests that the alterations in ventilatory control at altitude are due to failure of peripheral chemoreceptor function.

Progesterone for Outpatient Treatment of Pickwickian Syndrome

Ten patients with the Pickwickian syndrome, characterized by obesity, hypoxemia, hypercapnia, polycythemia, and cor pulmonale, underwent long-term treatment as outpatients with medroxyprogesterone acetate. Although there was no significant weight change in the group, PaO2 rose 12.6 +/- 2.7 mm Hg (SEM) from 49 +/- 2.6 mm Hg to 62 +/- 2.3 mm Hg (P less than 0.001), while PaCO2 fell 13 +/- 2.6 mm Hg from 51 +/- 1.9 mm Hg to 38 +/- 1.2 mm Hg (P less than 0.001). Hematocrit fell from 56 +/- 2.5% to 50 +/- 1.2%, a mean fall of 6% (P less than 0.01), during medroxyprogesterone acetate therapy. In the 2 patients who had cardiac catheterization before and during medroxyprogesterone acetate therapy, mean pulmonary arterial pressure fell 13 and 19 mm Hg. There were no recurrences of cor pulmonale during treatment. These effects on arterial blood gas values and clinical state were sustained during therapy. On withdrawal of medroxyprogesterone acetate during 1-month period, arterial oxygen and carbon dioxide tensions deteriorated to their previous pretreatment values. Reinstitution of medroxyprogesterone acetate caused improvement in both the oxygen and carbon dioxide tensions. We conclude that sublingual medroxyprogesterone acetate therapy is useful in the management of the Pickwickian syndrome.