Peripheral chemoreflex responsiveness is increased at elevated levels of carbon dioxide after episodic hypoxia in awake humans

We hypothesized that the acute ventilatory response to hypoxia is enhanced after exposure to episodic hypoxia in awake humans. Eleven subjects completed a series of rebreathing trials before and after exposure to eight 4-min episodes of hypoxia. During the rebreathing trials, subjects initially hyperventilated to reduce the partial pressure of carbon dioxide (PetCO2) below 25 Torr. Subjects then breathed from a bag containing normocapnic (42 Torr), low (50 Torr), or high oxygen (140 Torr) gas mixtures. During the trials, PetCO2 increased while a constant oxygen level was maintained. The point at which ventilation began to rise in a linear fashion as PetCO2 increased was considered to be the ventilatory recruitment threshold. The ventilatory response below and above the recruitment threshold was determined. Ventilation did not persist above baseline values immediately after exposure to episodic hypoxia; however, PetCO2 levels were reduced compared with baseline. In contrast, compared with baseline, the ventilatory response to progressive increases in carbon dioxide during rebreathing trials in the presence of low but not high oxygen levels was increased after exposure to episodic hypoxia. This increase occurred when carbon dioxide levels were above but not below the ventilatory recruitment threshold. We conclude that long-term facilitation of ventilation (i.e., increases in ventilation that persist when normoxia is restored after episodic hypoxia) is not expressed in awake humans in the presence of hypocapnia. Nevertheless, despite this lack of expression, the acute ventilatory response to hypoxia in the presence of hypercapnia is increased after exposure to episodic hypoxia.

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Ventilatory responses to carbon dioxide at low and high levels of oxygen are elevated after episodic hypoxia in men compared with women

Journal of Applied Physiology ◽

10.1152/japplphysiol.00541.2004 ◽

2004 ◽

Vol 97 (5) ◽

pp. 1673-1680 ◽

Cited By ~ 48

Author(s):

Chris Morelli ◽

M. Safwan Badr ◽

Jason H. Mateika

Keyword(s):

Carbon Dioxide ◽

Ventilatory Response ◽

Minute Ventilation ◽

High Oxygen ◽

Set Point ◽

Ventilatory Responses ◽

Episodic Hypoxia ◽

Before And After ◽

Oxygen Gas ◽

End Tidal

We hypothesized that the acute ventilatory response to carbon dioxide in the presence of low and high levels of oxygen would increase to a greater extent in men compared with women after exposure to episodic hypoxia. Eleven healthy men and women of similar race, age, and body mass index completed a series of rebreathing trials before and after exposure to eight 4-min episodes of hypoxia. During the rebreathing trials, subjects initially hyperventilated to reduce the end-tidal partial pressure of carbon dioxide (PetCO2) below 25 Torr. Subjects then rebreathed from a bag containing a normocapnic (42 Torr), low (50 Torr), or high oxygen gas mixture (150 Torr). During the trials, PetCO2 increased while the selected level of oxygen was maintained. The point at which minute ventilation began to rise in a linear fashion as PetCO2 increased was considered to be the carbon dioxide set point. The ventilatory response below and above this point was determined. The results showed that the ventilatory response to carbon dioxide above the set point was increased in men compared with women before exposure to episodic hypoxia, independent of the oxygen level that was maintained during the rebreathing trials (50 Torr: men, 5.19 ± 0.82 vs. women, 4.70 ± 0.77 l·min−1·Torr−1; 150 Torr: men, 4.33 ± 1.15 vs. women, 3.21 ± 0.58 l·min−1·Torr−1). Moreover, relative to baseline measures, the ventilatory response to carbon dioxide in the presence of low and high oxygen levels increased to a greater extent in men compared with women after exposure to episodic hypoxia (50 Torr: men, 9.52 ± 1.40 vs. women, 5.97 ± 0.71 l·min−1·Torr−1; 150 Torr: men, 5.73 ± 0.81 vs. women, 3.83 ± 0.56 l·min−1·Torr−1). Thus we conclude that enhancement of the acute ventilatory response to carbon dioxide after episodic hypoxia is sex dependent.

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Effect of episodic hypoxia on the susceptibility to hypocapnic central apnea during NREM sleep

Journal of Applied Physiology ◽

10.1152/japplphysiol.00308.2009 ◽

2010 ◽

Vol 108 (2) ◽

pp. 369-377 ◽

Cited By ~ 41

Author(s):

Susmita Chowdhuri ◽

Irina Shanidze ◽

Lisa Pierchala ◽

Daniel Belen ◽

Jason H. Mateika ◽

...

Keyword(s):

Mechanical Ventilation ◽

Ventilatory Response ◽

Recovery Period ◽

Positive Pressure ◽

Central Apnea ◽

Hypoxic Ventilatory Response ◽

Episodic Hypoxia ◽

Before And After ◽

Long Term Facilitation

We hypothesized that episodic hypoxia (EH) leads to alterations in chemoreflex characteristics that might promote the development of central apnea in sleeping humans. We used nasal noninvasive positive pressure mechanical ventilation to induce hypocapnic central apnea in 11 healthy participants during stable nonrapid eye movement sleep before and after an exposure to EH, which consisted of fifteen 1-min episodes of isocapnic hypoxia (mean O2 saturation/episode: 87.0 ± 0.5%). The apneic threshold (AT) was defined as the absolute measured end-tidal Pco2 (PetCO2) demarcating the central apnea. The difference between the AT and baseline PetCO2 measured immediately before the onset of mechanical ventilation was defined as the CO2 reserve. The change in minute ventilation (V̇I) for a change in PetCO2 (ΔV̇I/ ΔPetCO2) was defined as the hypocapnic ventilatory response. We studied the eupneic PetCO2, AT PetCO2, CO2 reserve, and hypocapnic ventilatory response before and after the exposure to EH. We also measured the hypoxic ventilatory response, defined as the change in V̇I for a corresponding change in arterial O2 saturation (ΔV̇I/ΔSaO2) during the EH trials. V̇I increased from 6.2 ± 0.4 l/min during the pre-EH control to 7.9 ± 0.5 l/min during EH and remained elevated at 6.7 ± 0.4 l/min the during post-EH recovery period ( P < 0.05), indicative of long-term facilitation. The AT was unchanged after EH, but the CO2 reserve declined significantly from −3.1 ± 0.5 mmHg pre-EH to −2.3 ± 0.4 mmHg post-EH ( P < 0.001). In the post-EH recovery period, ΔV̇I/ΔPetCO2 was higher compared with the baseline (3.3 ± 0.6 vs. 1.8 ± 0.3 l·min−1·mmHg−1, P < 0.001), indicative of an increased hypocapnic ventilatory response. However, there was no significant change in the hypoxic ventilatory response (ΔV̇I/ΔSaO2) during the EH period itself. In conclusion, despite the presence of ventilatory long-term facilitation, the increase in the hypocapnic ventilatory response after the exposure to EH induced a significant decrease in the CO2 reserve. This form of respiratory plasticity may destabilize breathing and promote central apneas.

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The Ventilatory Response to Hypoxia Below the Carbon Dioxide Threshold

Canadian Journal of Applied Physiology ◽

10.1139/h97-003 ◽

1997 ◽

Vol 22 (1) ◽

pp. 23-36 ◽

Cited By ~ 39

Author(s):

Theodore Rapanos ◽

James Duffin

Keyword(s):

Carbon Dioxide ◽

Partial Pressure ◽

Ventilatory Response ◽

Pressure Threshold ◽

Partial Pressures ◽

Progressive Hypoxia ◽

End Tidal ◽

Peripheral Chemoreflex ◽

Ventilatory Response To Hypoxia ◽

Lower Carbon

The ventilatory response to acute progressive hypoxia below the carbon dioxide threshold using rebreathing was investigated. Nine subjects rebreathed after 5 min of hyperventilation to lower carbon dioxide stores. The rebreathing bag initially contained enough carbon dioxide to equilibrate alveolar and arterial partial pressures of carbon dioxide to the lowered mixed venous partial pressure (≈ 30 mmHg), and enough oxygen to establish a chosen end-tidal partial pressure (50-70 mmHg), within one circulation time. During rebreathing, end-tidal partial pressure of carbon dioxide increased while end-tidal partial pressure of oxygen fell. Ventilation increased linearly with end-tidal carbon dioxide above a mean end-tidal partial pressure threshold of 39 ± 2.7 mmHg. Below this peripheral-chemoreflex threshold, ventilation did not increase, despite a progressive fall in end-tidal oxygen partial pressure to a mean of 37 ± 4.1 mmHg. In Conclusion, hypoxia does not stimulate ventilation when carbon dioxide is below its peripheral-chemoreflex threshold. Key words: peripheral chemoreflex, rebreathing technique, hyperventilation

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Influences of Morphine on the Ventilatory Response to Isocapnic Hypoxia

Anesthesiology ◽

10.1097/00000542-199706000-00016 ◽

1997 ◽

Vol 86 (6) ◽

pp. 1342-1349 ◽

Cited By ~ 44

Author(s):

Aad Berkenbosch ◽

Luc J. Teppema ◽

Cees N. Olievier ◽

Albert Dahan

Keyword(s):

Carbon Dioxide ◽

Steady State ◽

Shape Parameter ◽

Ventilatory Response ◽

Depressant Effect ◽

Ventilatory Responses ◽

Before And After ◽

End Tidal ◽

Ventilatory Response To Hypoxia ◽

Carbon Dioxide Sensitivity

Background The ventilatory response to hypoxia is composed of the stimulatory activity from peripheral chemoreceptors and a depressant effect from within the central nervous system. Morphine induces respiratory depression by affecting the peripheral and central carbon dioxide chemoreflex loops. There are only few reports on its effect on the hypoxic response. Thus the authors assessed the effect of morphine on the isocapnic ventilatory response to hypoxia in eight cats anesthetized with alpha-chloralose-urethan and on the ventilatory carbon dioxide sensitivities of the central and peripheral chemoreflex loops. Methods The steady-state ventilatory responses to six levels of end-tidal oxygen tension (PO2) ranging from 375 to 45 mmHg were measured at constant end-tidal carbon dioxide tension (P[ET]CO2, 41 mmHg) before and after intravenous administration of morphine hydrochloride (0.15 mg/kg). Each oxygen response was fitted to an exponential function characterized by the hypoxic sensitivity and a shape parameter. The hypercapnic ventilatory responses, determined before and after administration of morphine hydrochloride, were separated into a slow central and a fast peripheral component characterized by a carbon dioxide sensitivity and a single offset B (apneic threshold). Results At constant P(ET)CO2, morphine decreased ventilation during hyperoxia from 1,260 +/- 140 ml/min to 530 +/- 110 ml/ min (P < 0.01). The hypoxic sensitivity and shape parameter did not differ from control. The ventilatory response to carbon dioxide was displaced to higher P(ET)CO2 levels, and the apneic threshold increased by 6 mmHg (P < 0.01). The central and peripheral carbon dioxide sensitivities decreased by about 30% (P < 0.01). Their ratio (peripheral carbon dioxide sensitivity:central carbon dioxide sensitivity) did not differ for the treatments (control = 0.165 +/- 0.105; morphine = 0.161 +/- 0.084). Conclusions Morphine depresses ventilation at hyperoxia but does not depress the steady-state increase in ventilation due to hypoxia. The authors speculate that morphine reduces the central depressant effect of hypoxia and the peripheral carbon dioxide sensitivity at hyperoxia.

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Influences of Subanesthetic Isoflurane on Ventilatory Control in Humans

Anesthesiology ◽

10.1097/00000542-199509000-00006 ◽

1995 ◽

Vol 83 (3) ◽

pp. 478-490. ◽

Cited By ~ 30

Author(s):

Maarten van den Elsen ◽

Albert Dahan ◽

Jacob DeGoede ◽

Aad Berkenbosch ◽

Jack van Kleef

Keyword(s):

Carbon Dioxide ◽

Healthy Volunteers ◽

Ventilatory Response ◽

Carbon Dioxide Tension ◽

Central Component ◽

Ventilatory Control ◽

Ventilatory Responses ◽

End Tidal ◽

Peripheral Chemoreflex ◽

Ventilatory Response To Hypoxia

Background The purpose of this study was to quantify in humans the effects of subanesthetic isoflurane on the ventilatory control system, in particular on the peripheral chemoreflex loop. Therefore we studied the dynamic ventilatory response to carbon dioxide, the effect of isoflurane wash-in upon sustained hypoxic steady-state ventilation, and the ventilatory response at the onset of 20 min of isocapnic hypoxia. Methods Study 1: Square-wave changes in end-tidal carbon dioxide tension (7.5-11.5 mmHg) were performed in eight healthy volunteers at 0 and 0.1 minimum alveolar concentration (MAC) isoflurane. Each hypercapnic response was separated into a fast, peripheral component and a slow, central component, characterized by a time constant, carbon dioxide sensitivity, time delay, and off-set (apneic threshold). Study 2: The ventilatory changes due to the wash-in of 0.1 MAC isoflurane, 15 min after the induction of isocapnic hypoxia, were studied in 11 healthy volunteers. Study 3: The ventilatory responses to a step decrease in end-tidal oxygen (end-tidal oxygen tension from 110 to 44 mmHg within 3-4 breaths; duration of hypoxia 20 min) were assessed in eight healthy volunteers at 0, 0.1, and 0.2 MAC isoflurane. Results Values are reported as means +/- SF. Study 1: The peripheral carbon dioxide sensitivities averaged 0.50 +/- 0.08 (control) and 0.28 +/- 0.05 l.min-1.mmHg-1 (isoflurane; P < 0.01). The central carbon dioxide sensitivities (control 1.20 +/- 0.12 vs. isoflurane 1.04 +/- 0.11 l.min-1.mmHg-1) and off-sets (control 36.0 +/- 0.1 mmHg vs. isoflurane 34.5 +/- 0.2 mmHg) did not differ between treatments. Study 2: Within 30 s of exposure to 0.1 MAC isoflurane, ventilation decreased significantly, from 17.7 +/- 1.6 (hypoxia, awake) to 15.0 +/- 1.5 l.min-1 (hypoxia, isoflurane). Study 3: At the initiation of hypoxia ventilation increased by 7.7 +/- 1.4 (control), 4.1 +/- 0.8 (0.1 MAC; P < 0.05 vs. control), and 2.8 +/- 0.6 (0.2 MAC; P < 0.05 vs. control) l.min-1. The subsequent ventilatory decrease averaged 4.9 +/- 0.8 (control), 3.4 +/- 0.5 (0.1 MAC; difference not statistically significant), and 2.0 +/- 0.4 (0.2 MAC; P < 0.05 vs. control) l.min-1. There was a good correlation between the acute hypoxic response and the hypoxic ventilatory decrease (r = 0.9; P < 0.001). Conclusions The results of all three studies indicate a selective and profound effect of subanesthetic isoflurane on the peripheral chemoreflex loop at the site of the peripheral chemoreceptors. We relate the reduction of the ventilatory decrease of sustained hypoxia to the decrease of the initial ventilatory response to hypoxia.

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Diphenhydramine Increases Ventilatory Drive during Alfentanil Infusion

Anesthesiology ◽

10.1097/00000542-199809000-00013 ◽

1998 ◽

Vol 89 (3) ◽

pp. 642-647. ◽

Cited By ~ 8

Author(s):

H. Daniel Babenco ◽

Robert T. Blouin ◽

Pattilyn F. Conard ◽

Jeffrey B. Gross

Keyword(s):

Carbon Dioxide ◽

Ventilatory Response ◽

Minute Ventilation ◽

Blood Levels ◽

Ventilatory Responses ◽

Ventilatory Drive ◽

Before And After ◽

End Tidal ◽

Carbon Dioxide Response ◽

Ventilatory Response To Hypoxia

Background Diphenhydramine is used as an antipruritic and antiemetic in patients receiving opioids. Whether it might exacerbate opioid-induced ventilatory depression has not been determined. Methods The ventilatory response to carbon dioxide during hyperoxia and the ventilatory response to hypoxia during hypercapnia (end-tidal pressure of carbon dioxide [PETCO2] is approximately equal to 54 mmHg) were determined in eight healthy volunteers. Ventilatory responses to carbon dioxide and hypoxia were calculated at baseline and during an alfentanil infusion (estimated blood levels approximately equal to 10 ng/ml) before and after diphenhydramine 0.7 mg/kg. Results The slope of the ventilatory response to carbon dioxide decreased from 1.08+/-0.38 to 0.79+/-0.36 l x min(-1) x mmHg(-1) (x +/- SD, P < 0.05) during alfentanil infusion; after diphenhydramine, the slope increased to 1.17+/-0.28 l x min(-1) x mmHg(-1) (P < 0.05). The minute ventilation (VE) at PETCO2 approximately equal to 46 mmHg (VE46) decreased from 12.1+/-3.7 to 9.7+/-3.6 l/min (P < 0.05) and the VE at 54 mmHg (VE54) decreased from 21.3+/-4.8 to 16.6+/-4.7 l/min during alfentanil (P < 0.05). After diphenhydramine, (VE46 did not change significantly, remaining lower than baseline at 9.9+/-2.9 l/min (P < 0.05), whereas VE54 increased significantly to 20.5+/-3.0 l/min. During hypoxia, VE at SpO2 = 90% (VE90) decreased from 30.5+/-9.7 to 23.1+/-6.9 l/min during alfentanil (P < 0.05). After diphenhydramine, the increase in VE90 to 27.2+/-9.2 l/min was not significant (P = 0.06). Conclusions Diphenhydramine counteracts the alfentanil-induced decrease in the slope of the ventilatory response to carbon dioxide. However, at PETCO2 = 46 mmHg, it does not significantly alter the alfentanil-induced shift in the carbon dioxide response curve. In addition, diphenhydramine does not exacerbate the opioid-induced depression of the hypoxic ventilatory response during moderate hypercarbia.

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Faculty Opinions recommendation of The ventilatory response to carbon dioxide and sustained hypoxia is enhanced after episodic hypoxia in OSA patients.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1027485.328570 ◽

2005 ◽

Author(s):

James Duffin

Keyword(s):

Carbon Dioxide ◽

Ventilatory Response ◽

Episodic Hypoxia ◽

Sustained Hypoxia

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Hypoxic-hypercapnic interaction in subjects with bilateral cerebral dysfunction

Journal of Applied Physiology ◽

10.1152/jappl.1963.18.6.1139 ◽

1963 ◽

Vol 18 (6) ◽

pp. 1139-1145 ◽

Cited By ~ 10

Author(s):

Fred Plum ◽

Harold W. Brown

Keyword(s):

Carbon Dioxide ◽

Brain Damage ◽

Pyramidal Tract ◽

Ventilatory Response ◽

Cerebral Dysfunction ◽

Tract Disease ◽

The Brain ◽

Carbon Dioxide Response ◽

Ventilatory Response To Hypoxia ◽

Respiratory Responses

To analyze cerebral influences modifying autonomic respiratory responses, we compared normals and patients with bilateral pyramidal tract disease for their ventilatory response to hypoxia and hypoxia-hypercapnia. During eucapnia, the two groups showed similar hypoxic responses. During hypercapnia, the ventilatory response to hypoxia was greater in the brain-damaged subjects. This apparent augmentation, however, was due entirely to anoxia interacting with an abnormally facilitated carbon dioxide sensitivity: compared with normals, brain-damaged patients at PaOO2 90–100 mm Hg showed an 85% greater CO2 response, and at PaOO2 50 mm Hg showed a 79% greater CO2 response. Since cerebral dysfunction facilitated the ventilatory response to hypoxia-hypercapnia combined but not the response to hypoxia alone, the results imply that the two respiratory stimuli interact centrally rather than peripherally. respiration; brain damage; interaction; carbon dioxide response; forebrain effects; ventilation with CNS disease Submitted on February 18, 1963

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