Almitrine increases the steady-state hypoxic ventilatory response in hypoxic chronic air-flow obstruction

Almitrine, a peripheral chemoreceptor agonist, exerts beneficial effects on blood gases in patients with hypoxic chronic air-flow obstruction, but as these patients exhibit poor ventilatory responses to hypoxia, the mechanism for this improvement is not clear. The effect of a 100-mg dose of almitrine given orally on ventilation and the steady-state hypoxic ventilatory response (HVR) were measured in a randomized, double-blind, placebo-controlled manner in 7 patients with severe hypoxic chronic air-flow obstruction. The isocapnic HVR (delta VE/delta SaO2) was calculated from the changes in ventilation and SaO2 from breathing 60% O2 to breathing air with the addition of CO2 to maintain isocapnia (as estimated from a transcutaneous CO2 electrode). Resting ventilation while breathing air and isocapnic HVR were measured before and 3 h after almitrine or placebo. Almitrine caused no significant change in resting ventilation. There was, however, a large increase in HVR after almitrine (almitrine: -1.5 L/min/%SaO2; range, -0.5 to -3.1; control: -0.4; range, -0.3 to -1.3), but no change after placebo. Almitrine is a powerful stimulant of chemosensitivity and of the hypoxic ventilatory response in chronic hypoxemia, with potential benefit to patients with chronic air-flow obstruction in respiratory failure.     

Almitrine and the peripheral ventilatory response to CO2 in hyperoxia and hypoxia

The effects of almitrine bismesylate (initial intravenous dose 0.6 mg.kg-1 followed by continuous infusion of 0.4 mg.kg-1.h-1) on the ventilatory response to CO2 during hyperoxia and hypoxia were determined in 6 anaesthetized cats with the use of the dynamic end-tidal CO2 forcing technique. It was found that almitrine almost doubled the peripheral ventilatory sensitivity to CO2 during hyperoxia (mean PETO2 45.6 kPa) and also during mild hypoxia (mean PETO2 8.7 kPa). The apnoeic threshold (B) was in both cases shifted to substantially lower values than those of the control measurements. No significant effects of almitrine were found on the central ventilatory sensitivity to CO2 either during hyperoxia or during hypoxia. It is argued that the decrease of the apnoeic threshold may be due to an inhibitory effect of almitrine on the carotid body dopaminergic activity, and that the increase of the sensitivity to CO2 stems from a "hypoxia mimetic" mechanism.     

Improvement in ventilation-perfusion relationships by almitrine in patients with chronic obstructive pulmonary disease during mechanical ventilation

Although the respiratory stimulant effects of almitrine bismesylate (AB) via an action on the peripheral chemoreceptors have been demonstrated, the mechanism of its intrapulmonary action has not yet been elucidated. In order to abolish the stimulation of ventilation, observed in studies on spontaneously breathing patients, an investigation of patients suffering from severe COPD under constant mechanical ventilation, with FIO2 = 0.21, during the weaning period was carried out. Eighteen patients were randomly divided into 2 groups (9 receiving 1.5 mg/kg AB and 9 receiving placebo). The ventilatory and hemodynamic variables, blood and alveolar gases, and the VA/Q ratio distributions using the multiple inert gas technique were collected before treatment with drug or placebo, as well as 90 and 180 min afterwards. The PaO2 was found to be raised 90 min after AB administration (+57 +/- 3.9 mm Hg, p less than 0.01) and remained above the baseline value at 180 min (+5.4 +/- 4.6 mm Hg, p less than 0.01). Compared with those in the placebo group, these increases were significant (p less than 0.01). A slight decrease in PaCO2 but similar in the 2 groups was observed despite constant ventilation. The hemodynamic data were the same for the 2 groups. The changes in overall criteria of the distributions (mean VA/Q and SD) were small. The main finding was a decrease in the percentage of the perfusion flowing through the true shunt and the underventilated areas after AB treatment. In the control group, the blood flow percentage in the true shunt and low VA/Q units was either stable or increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

A single orally administered dose of almitrine improves pulmonary gas exchange during exercise in patients with chronic air-flow obstruction

To verify if the improvement in gas exchange observed at rest with almitrine in patients with chronic air-flow obstruction is maintained at exercise, we studied 10 patients on a randomized, crossover, double-blind exercise protocol. After assessment of steady state of their disease, patients with FEV 1 less than 1.5 L.s-1 and PaCO2 less than 70 mmHg cycled 8 to 11 min at 80% of their previously determined maximal O2 uptake. Blood gases, arterial lactate (La), expired ventilation, (VE), O2 uptake (Vo2), Co2 production (VCO2), heart rate (HR), and arterial blood pressure (BP) were measured at rest, at mid-exercise, at end-exercise, and at 2, 14, 15, and 35 min of recovery. We found that at all stages of the study PaO2 was significantly higher in those who had received almitrine than in those who had received placebo; the mean increment was 11.9 torr at rest, 8.9 at end-exercise, and 13.7 at 15 min of recovery. Changes in PaCO2 and arterial (H+) were the opposite of those in PaO2; at end-exercise PaCO2 was 5.9 torr lower in those who had received almitrine, and pH was 7.36 versus 7.32 in those who had received placebo. No significant difference was found at all stages of the study between drug and placebo with respect to VE, VO2, VCO2, HR, and BP. But the ventilatory equivalent for oxygen, VE/VO2, was slightly higher in those who had received almitrine than in those who had received placebo during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of domperidone and medroxyprogesterone acetate on ventilation in man

If endogenous dopamine acts as an inhibitory neurotransmitter in the carotid bodies in man, domperidone (DP), a selective dopamine D-2 receptor antagonist should stimulate carotid bodies and augment ventilation. Furthermore, the combination of a central ventilatory stimulant, medroxyprogesterone acetate (MPA), with a peripheral ventilatory stimulant, DP, may produce an additive/synergistic ventilatory effect. We conducted a double-blind, placebo-controlled (P), cross-over trial comparing MPA 20 mg three times daily (TID) and DP (20 mg TID) alone and together in 8 healthy male human subjects. Drug effects were measured after 7 days, and a two-week drug washout period was allowed. MPA significantly increased alveolar ventilation (VA), and slopes of hypercapnic and hypoxic ventilatory responses. Domperidone alone significantly increased the slope of the hypoxic response; however, VA and PaCO2 did not change significantly. The combination of MPA and DP resulted in ventilatory changes similar to MPA alone. We conclude that in man endogenous dopamine acts as a modulator of chemoreception during hypoxemia, but plays no major role tonically in control of ventilation during normoxemia and normocapnia. Lack of additive effect with combined DP and MPA suggests that these drugs may share the same final common pathway in the process of chemoreception.     

Domperidone-induced potentiation of ventilatory responses in awake goats

Dopamine has been implicated in maintaining tonic inhibition of carotid body activity. We tested this hypothesis by assessing the ventilatory effects of a peripheral dopamine antagonist, domperidone. The effects of this agent on the ventilatory responses to hypoxia and hypercapnia were also examined. The study was performed in awake carotid body intact and carotid body denervated goats. Resting minute ventilation increased while PaCO2 decreased (4 Torr) following domperidone administration (0.5 mg/kg, I.V.) in carotid body intact goats. This response did not occur in carotid body denervated goats supporting the hypothesis that endogenous dopamine provides tonic inhibition in the carotid body. Hypoxic and hypercapnic ventilatory responses were significantly augmented following domperidone administration in the carotid body intact goats. This supports the concept of dopaminergic modulation of the response of the carotid body to stimuli. Domperidone allows study of carotid chemoreceptor dopaminergic activity in awake animals because of its high affinity for carotid body D2 dopamine receptors and its lack of CNS effects.     

Breathing pattern--gas exchange relation and acute effect of almitrine in severe chronic airflow obstruction

Using a double-blind cross-over design, a single oral dose of 100 mg almitrine bismethylate and placebo were administered to 7 patients with chronic airflow limitation. In all patients, arterial blood gases at rest, ventilation and breathing pattern at rest and on exercise were measured before and 3 h after administration. Ventilation increased and PaCO2 decreased after almitrine; the mean PaO2 increase was statistically significant after active drug but the value increased more when tidal volume increased. It is concluded that in man the well-documented improvement in the V/Q relationship after almitrine is in part related to a pure ventilatory effect though the possibility of increasing ventilation by mainly increasing tidal volume.     

Role of beta adrenergic receptors in carotid body function of the goat

Previous studies in anesthetized or decerebrate cats and rabbits and awake man have shown conflicting results regarding a potential role for beta-adrenergic receptors in carotid body function. Therefore, we sought to clarify the role of beta-adrenergic receptor activity in carotid body function by assessing: the ventilatory response to intravenous isoproterenol infusion in awake and anesthetized carotid body intact and carotid body denervated goats, the effect of propranolol on the ventilatory response to isocapnic hypoxemia, and carotid sinus nerve chemoreceptor discharge rate response to isoproterenol and hypoxia. Isoproterenol increased ventilation to a similar degree in carotid body intact and denervated awake and anesthetized goats. This ventilatory increase was blocked by propranolol. Propranolol did not alter the hypoxic ventilatory response. Although ventilation increased, carotid sinus nerve chemoreceptor discharge rate was not altered by isoproterenol infusion or bolus IV injection in anesthetized goats. Hypoxia did increase carotid sinus nerve discharge rate. In this study, beta-adrenergic stimulation of ventilation did not occur via the carotid body, and beta-adrenergic blockade did not affect the carotid body hypoxic ventilatory response. Therefore, we found no evidence of functional beta-adrenergic activity within the carotid body of the goat.     

The effect of almitrine bismesylate on the steady-state responses of arterial chemoreceptors to CO2 and O2 in the cat

The interaction between almitrine bismesylate, a pharmacological stimulant of peripheral chemoreceptors, and varying levels of oxygen (PO2 50-600 Torr) and carbon dioxide (PCO2 10-65 Torr) on steady state carotid chemoreceptor discharge was investigated in pentobarbitone-anaesthetised cats. Almitrine was given as constant intravenous (50 micrograms/kg per min for 4 min) and intracarotid infusions (4-16 micrograms/kg per min) at different levels of alveolar PO2 and PCO2. Almitrine always excited discharge. The intracarotid infusions at the lower infusion rate (4-8 micrograms/kg per min) and the i.v. infusions increased the slope of the isoxic response to CO2. This effect could be reversed by raising PO2 to high levels. Higher infusion rates of almitrine (16 micrograms/kg per min) displaced the CO2 response curve upwards but did not increase its slope above that obtained in control conditions at end-tidal PO2 of 50 Torr. However, as these higher infusion rates caused levels of discharge greater than those achieved during control conditions, their effects on control CO2 sensitivity could not be ascertained. Our results suggest that almitrine excites carotid body chemoreceptors by a mechanism similar to that of hypoxia and not like that of carbon dioxide.     

Chemoreceptive mechanisms elucidated by studies of congenital central hypoventilation syndrome.

Humans born with the condition of central hypoventilation during non-rapid eye movement sleep, termed congenital central hypoventilation syndrome (CCHS), invariably have absent or greatly diminished central hypercapnic ventilatory chemosensitivity. Genetic and pathological studies of CCHS may enable identification of the genes or areas of the central nervous system involved in the syndrome and thus implicated in central hypercapnic ventilatory chemosensitivity. Functional studies of CCHS permit a more quantitative assessment of the importance of ventilatory chemosensitivity in the regulation of breathing during wakefulness and sleep. The experimental evidence suggests that central hypercapnic ventilatory chemosensitivity is crucial in regulating alveolar ventilation during non-rapid eye movement sleep but not during rapid eye movement sleep or during many of the behaviors occurring during wakefulness. Presumably, other neural drives to breathe supervene to enable adequate ventilation. However, although physiological studies in CCHS subjects have been greatly instructive, their accurate interpretation will have to await future determination of the potential genetic and/or neuroanatomic basis of the syndrome.     

The effect of intravenously administered almitrine, a peripheral chemoreceptor agonist, on patients with chronic air-flow obstruction

Almitrine, a peripheral chemoreceptor agonist, was given intravenously in a dose of 0.5 mg/kg/h for 2 h in a randomized double-blind manner with placebo, to 11 patients with severe chronic air-flow obstruction and hypoxemia (SaO2 less than 90%). There was no significant placebo effect. Maximal respiratory effect occurred at the end of the almitrine infusion with an increase in ventilation from 8.2 + 0.9 to 11.6 + 1.5 L/min (mean +/- SEM), and improvements in SaO2 from 83 +/- 3 to 90 +/- 2%, in PaO2 from 48 +/- 2 to 55 +/- 3 mmHg, and in PaCO2 from 54 + 3 to 47 +/- 4 mmHg. Venous admixture was reduced from 38 +/- 4% to 22 +/- 3%. In 4 patients, blood gas values substantially improved, but there was no change in total ventilation for ventilatory pattern. This study of acute effects showed that almitrine improved arterial PO2 and PCO2 in patients with chronic air-flow obstruction both by increasing ventilation and by improving ventilation-perfusion relationships.     

Long-term survival of a patient with congenital central hypoventilation syndrome despite the lack of continuous ventilatory support

Untreated idiopathic congenital central hypoventilation syndrome (CCHS) is thought to cause infant death within 1-2 months. Here we present an adult patient with CCHS who survived without continuous ventilatory support, despite hypoventilation from early childhood onward. The diagnosis was confirmed at the age of 22 years, when the patient presented with hypoventilation during the night (PaCO2 60 mm Hg, PaO2 56 mm Hg, pH 7.32 HCO3- 30 mmol/l) but hyperventilation when awake (PaCO2 26 mm Hg, PaO2 81 mm Hg, pH 7.56, HCO3- 23 mmol/l). The maximal hematocrit was 77%. Despite mental retardation, noninvasive positive pressure ventilation (NPPV) could be successfully established. NPPV-supported ventilation during the night (PaCO2 36, PaO2 84 mm Hg, pH 7.47, HCO3- 25 mmol/l) reduced hematocrit values (40.6 to 36.8%) over a period of 4 years. In conclusion, long-term survival with CCHS is possible without continuous ventilatory support. Spontaneous improvement of hypoventilation during sleep throughout childhood is possible and hyperventilation during wakefulness may occur in patients with CCHS. CCHS can be managed with NPPV despite mental retardation, even over a long-term period.     

Hypercapnic and hypoxic ventilatory responses in parents and siblings of children with congenital central hypoventilation syndrome

Children with congenital central hypoventilation syndrome (CCHS) have abnormal ventilatory responses to metabolic stimuli. As there is a genetically determined component of chemoreceptor sensitivity, parents and siblings of children with CCHS may also have blunted ventilatory responses to hypercapnea and hypoxia. To test this, we studied hypercapnic ventilatory responses and hypoxic ventilatory responses in six mothers, four fathers, and five siblings (6 to 49 yr of age) of seven children with CCHS and compared them with 15 age- and sex-matched control subjects (5 to 47 yr of age). Pulmonary function tests were not different between relatives of children with CCHS and control subjects. To measure hypercapnic ventilatory responses, subjects rebreathed 5% CO2/95% O2 until PACO2 reached 60 to 70 mm Hg. To measure hypoxic ventilatory responses (L/min/% SaO2), subjects rebreathed 14% O2/7% CO2/balance N2 at mixed venous PCO2 until SaO2 fell to 75%. All tests were completed in less than 4 min. Instantaneous minute ventilation, mean inspiratory flow (tidal volume/inspiratory time), and respiratory timing (inspiratory timing/total respiratory cycle timing) were calculated on a breath-by-breath basis. Hypercapnic ventilatory responses were 1.97 +/- 0.32 L/min/mm Hg PACO2 in children with CCHS relatives and 2.23 +/- 0.23 L/min/mm Hg PACO2 in control subjects. Hypoxic ventilatory responses were -1.99 +/- 0.37 L/min/% SaO2 in the relatives and -1.54 +/- 0.25 L/min/% SaO2 in the control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of combined morphine and prochlorperazine on ventilatory control in humans

Recent studies have shown that the antiemetic neuroleptic drug, prochlorperazine, is a potent stimulant of the ventilatory response to hypoxia. To investigate whether or not this effect persisted in the presence of central depression of ventilatory drive, the effects on ventilatory control of morphine with and without prochlorperazine were studied in 12 normal humans. Measurement of resting ventilation and the ventilatory responses to progressive hypercapnia and to transient asphyxia were made before and 15 min after morphine (0.15 mg/kg) given intravenously. Prochlorperazine (12.5 mg) was then administered intravenously to 6 study subjects and saline to 6 control subjects. After a further 10 min, resting ventilation and chemoreceptor function were remeasured. After the administration of morphine, resting ventilation, the ventilatory response to hypercapnia, and the ventilatory response to asphyxia were all significantly decreased (p less than 0.01 in each case; mean effect in control and study group were, respectively, -16 and -17%, -50 and -32%, -46 and -55%). Administration of saline produced no significant additional changes in the 6 control subjects. By contrast, administration of prochlorperazine to the 6 study subjects markedly increased the ventilatory response to asphyxia to levels significantly greater than postmorphine values (p less than 0.005; 2.38 +/- 0.22 L . min-1 . % Sao2 versus 0.80 +/- 0.14 L . min-1; mean +/- SEM). Resting ventilation and ventilatory response to hypercapnia were not significantly affected by prochlorperazine. These results were not explained by differences in end-tidal PCO2 at which hypercapnic hypoxic tests were performed. It is concluded that prochlorperazine reverses the depression of the ventilatory response to asphyxia caused by morphine.     

Effects of changes in tidal volume on avian intrapulmonary chemoreceptor discharge

It has been suggested that avian intrapulmonary CO2-sensitive receptors (IPC) may be capable of monitoring the rate and extent of CO2 washout from the lung during spontaneous breathing. The purpose of this study was to analyse IPC discharge activity (using computerised bin-averaging and counting techniques) in spontaneously breathing domestic fowl when VT was elevated from resting levels. This was accomplished by administration of almitrine (2 mg X kg-1 i.v.), a respiratory stimulant drug that has been shown to have a specific long-lasting stimulatory action on carotid body chemoreceptors. Unanaesthetized decerebrate chickens were tracheotomized and single unit activity was recorded from 14 IPC. When VT progressively increased following administration of almitrine (with little or no change in TI or TE), IPC activity increased in a linear relationship with the increased VT. IPC activity in expiration was also increased, and the delay period before the onset of IPC discharge in inspiration was shortened. It is concluded that IPC discharge is increased when VT is elevated in the spontaneously breathing chicken and hence the IPC are capable of monitoring the extent of each ventilatory effort. It is well known that IPC have strong inhibitory effects on ventilatory motor output and conceivably they could originate reflexogenic information to the respiratory centres in response to intrapulmonary PCO2 changes. The latter could arise from changes in CO2 delivery by the mixed venous blood or from changes in the extent of CO2 washout with each breath.     

Mother-daughter transmission of congenital central hypoventilation syndrome

The cause of congenital central hypoventilation syndrome (CCHS) is unknown, but a genetic etiology is strongly suspected. We report a 25-year-old woman with CCHS (no Hirschsprung's disease) who gave birth to a daughter who also has CCHS. This suggests a dominant mode of inheritance for CCHS in this family. Pregnancy can be associated with physiologic challenges in CCHS. The increase in endogenous progesterone may stimulate breathing and may possibly improve symptoms of hypoventilation. Although this patient did not have any worsening in symptoms, her hyperoxic hypercapnic rebreathing ventilatory response was not different when pregnant versus when not pregnant. Ventilatory support for the patient was successfully managed with diaphragm pacing throughout the pregnancy without the need to adjust settings, despite the enlarged abdomen during pregnancy. We conclude that CCHS may be an inherited disorder. Increased endogenous progesterone during pregnancy has no effect on the ventilatory response, and diaphragm pacing can successfully provide adequate ventilation throughout pregnancy.     

Effect of almitrine on ventilation-perfusion distribution in adult respiratory distress syndrome

Almitrine improves ventilation/perfusion relationships (VA/Q) in COPD, but its effects in ARDS, in which VA/Q mismatching is the cause of severe hypoxemia, are not known. The effects of almitrine on pulmonary gas exchange and circulation were assessed in 9 patients with ARDS who were sedated, paralyzed, and mechanically ventilated at constant FlO2 (range, 0.48 to 0.74). Systemic and pulmonary hemodynamics, conventional gas exchange, and the VA/Q distribution by the multiple inert gas elimination technique (MIGT) were measured before (baseline), during (ALM 15), at the end of (ALM 30), and at 30-min intervals after (POSTALM 30, 60, and 90) the intravenous infusion of 0.5 mg/kg body weight of almitrine over 30 min. Almitrine significantly increased PaO2 from 78 +/- 15 mm Hg to 140 +/- 49 at ALM 15 and 138 +/- 52 at ALM 30. AaPO2 and QS/QT decreased during the administration of the drug. The MIGT showed that almitrine redistributed pulmonary blood flow from shunt areas (reduction from 29 +/- 11 to 17 +/- 11% of QT) to lung units with normal VA/Q ratios (increase from 63 +/- 9 to 73 +/- 6% of QT). The Ppa increased from 26 +/- 5 to 30 +/- 5 mm Hg without changes in QT. Changes were transient, returning toward baseline 30 min after stopping the infusion of the drug. Almitrine significantly reduced the VA/Q inequalities present in ARDS and may be useful in the management of those patients.     

Dose-response and pharmacokinetic study with almitrine bismesylate after single oral administrations in COPD patients

To better define the dose-effect relationship and the pharmacokinetics of almitrine, sixteen stable hypoxaemic COPD patients received random single oral administrations of almitrine bismesylate 50, 100 and 150 mg or placebo at two-week intervals in a double-blind manner. Resting ventilation, arterial blood gases and plasma almitrine levels were measured. No significant changes were seen after placebo administration. Almitrine 50 and 100 mg caused a significant dose-related improvement in arterial oxygen tension (PaO2) in thirteen of the sixteen patients. Almitrine 150 mg caused little if any additional PaO2 increment. PaO2 returned to near basal values after 24 h. Two patients responded to almitrine 100 and 150 mg only, whereas one patient did not respond at all. Mean PaO2 increases in the sixteen patients were 0.9 kPa (7 mmHg), 1.5 kPa (11 mmHg) and 1.6 kPa (12 mmHg) 3 h after 50, 100 and 150 mg, respectively. A significant mean 0.9 kPa (7 mmHg) decrease in arterial carbon dioxide tension (PaCO2) and a l.min-1 increase in ventilation were observed after almitrine 150 mg. Mean maximum almitrine plasma concentration and area under the curve correlated linearly with dose. The relationship between mean PaO2 improvement and mean almitrine plasma level was curvilinear with a flattening of the curve over plasma levels of 150 ng.ml-1. Almitrine plasma half-life was found to be 116-140 h.     

An ode to George Polgar: Founding father of Pediatric pulmonology

Children with congenital central hypoventilation syndrome (CCHS) lack normal awake ventilatory responses to hypoxia and hypercarbia, yet engage in daily activities typical of similarly aged children. Our patients with CCHS are assessed annually with a walking treadmill protocol to assess physiologic responses to different levels of simulated daily activity. We hypothesized that children with CCHS (compared with age- and sex-matched healthy controls) would (1) exercise for shorter durations and reach lower peak speed and incline on the treadmill; (2) become more hypoxemic, more hypercarbic, and develop less tachycardia during activity; and (3) take longer to return to baseline oxygenation, ventilation, and heart rate than normal children. Seven children with CCHS [mean age, 6.9 ± 3.0 (SD) years] who required 24 h/day ventilatory support (diaphragm pacers while awake and mechanical ventilation asleep) and 7 controls performed a walking protocol on a treadmill with progressive increments in speed and incline. Hemoglobin saturations (SaO₂), end-tidal carbon dioxide concentrations (E_TCO₂), and heart rates (HR) were recorded at baseline conditions, during activity and during recovery. There were no significant differences between children with CCHS and controls in baseline values, duration of activity, peak speed, and incline achieved during walking and recovery time to baseline once the treadmill had stopped. However, children with CCHS became significantly more hypoxemic and hypercarbic during activity (P < 0.05), and they had a lower percent increase in HR during treadmill walking than controls (P < 0.05). These results offer the clinician an opportunity to adjust clinical management in children with CCHS by providing specific recommendations to parents about appropriate levels of activity for their children with CCHS. Although such was not the intent of the current research, this study will suggest further investigation into improved ventilatory support for these children during exercise. Pediatr Pulmonol. 1995; 20:89–93 . © 1995 Wiley-Liss, Inc.     

Passive motion of the extremities modifies alveolar ventilation during sleep in patients with congenital central hypoventilation syndrome

Passive motion of lower extremities (PMLE) elicits significant increases in alveolar ventilation (V A) in awake children with congenital central hypoventilation syndrome (CCHS), who have absent or near absent ventilatory responses to hypercapnia. We hypothesized that PMLE would improve V A during non-rapid eye movement (NREM) sleep. To study this, six patients with CCHS (0.2 to 7 yr of age) were disconnected from mechanical ventilatory support during Stage III-IV NREM, and their feet were passively moved at the ankle, either manually or with a motorized device strapped to their feet at 40 to 50 strokes/min. Holding of the feet without motion served as control (C). From a total of 74 successful trials not associated with sleep state changes, PET(CO(2)) decreased from 58.9 +/- 3.5 to 40.9 +/- 2.6 mm Hg with PMLE (n = 58; p < 0.001), whereas end-tidal carbon dioxide (PET(CO(2))) increased in C (n = 16; 58.8 +/- 3.1 to 60.3 +/- 3.7 mm Hg; PMLE versus C: p < 0.001). PMLE increased respiratory frequency from 10.2 +/- 1.9 to 21.2 +/- 2.7 breaths/min (p < 0.0001). We conclude that PMLE during NREM increases V A possibly via activation of mechanoreceptor-afferent pathways rather than by respiratory entrainment. We speculate that such effect may provide future noninvasive ventilatory support strategies in patients with CCHS and mild phenotypic expression of their disease.