Central CO2 Responsiveness Research Articles

An act of balance: Interaction of central and peripheral chemosensitivity with inflammatory and anti-inflammatory factors in obstructive sleep apnoea

ObjectivesCentral and peripheral chemosensitivity i.e. ventilatory response to CO2 and O2 are thought to be decisive for ventilatory control instability in obstructive sleep apnoea (OSA). Obesity is associated with chronic low level inflammation. Whether body mass related inflammatory and anti-inflammatory factors influencing peripheral and central chemosensitivity differentially is unclear. MethodsVentilatory response to hypercapnic-hyperoxic and hypercapnic-hypoxic gas mixtures in patients with OSA (n = 46) and healthy individuals (n = 45) was measured. C-reactive protein (CRP), leptin, adiponectin, and endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) were measured in blood samples. ResultsMediation analysis revealed that association of chemoresponse to CO2 with apnoea hypopnea index (AHI) was fully mediated by body mass index (BMI). Regression analysis showed that CRP and leptin levels explained ˜25% and ˜15% of the variance in central CO2 response, while 2-AG explained ˜42% of the variance in peripheral response to hypoxia. ConclusionInflammatory and anti-inflammatory factors could explain differential alterations in peripheral and central ventilatory chemoresponse in patients with OSA.

The rostral medulla of bullfrog tadpoles contains critical lung rhythmogenic and chemosensitive regions across metamorphosis

The development of amphibian breathing provides insight into vertebrate respiratory control mechanisms. Neural oscillators in the rostral and caudal medulla drive ventilation in amphibians, and previous reports describe ventilatory oscillators and CO2 sensitive regions arise during different stages of amphibian metamorphosis. However, inconsistent findings have been enigmatic, and make comparisons to potential mammalian counterparts challenging. In the current study we assessed amphibian central CO2 responsiveness and respiratory rhythm generation during two different developmental stages. Whole-nerve recordings of respiratory burst activity in cranial and spinal nerves were made from intact or transected brainstems isolated from tadpoles during early or late stages of metamorphosis. Brainstems were transected at the level of the trigeminal nerve, removing rostral structures including the nucleus isthmi, midbrain, and locus coeruleus, or transected at the level of the glossopharyngeal nerve, removing the putative buccal oscillator and caudal medulla. Removal of caudal structures stimulated the frequency of lung ventilatory bursts and revealed a hypercapnic response in normally unresponsive preparations derived from early stage tadpoles. In preparations derived from late stage tadpoles, removal of rostral or caudal structures reduced lung burst frequency, while CO2 responsiveness was retained. Our results illustrate that structures within the rostral medulla are capable of sensing CO2 throughout metamorphic development. Similarly, the region controlling lung ventilation appears to be contained in the rostral medulla throughout metamorphosis. This work offers insight into the consistency of rhythmic respiratory and chemosensitive capacities during metamorphosis.

Physiological insights of exercise hyperventilation in arterial and chronic thromboembolic pulmonary hypertension

BackgroundPulmonary hypertension (PH) patients show, during exercise, an excessive increase in ventilation (VE) compared to carbon dioxide output (VCO2), determining a high VE/VCO2 slope. There are several possible causes, including an elevated dead space ventilation (VD), VE/perfusion (Q) mismatch and/or an enhanced peripheral or central chemoreceptor activity. We evaluated the causes of exercise hyperventilation in PH patients. MethodsEighteen group I and IV PH patients underwent cardiopulmonary exercise test with blood gas analysis at every minute. VE, alveolar ventilation (VA) and VD vs. VCO2 relationship were calculated. Resting chemoreceptor sensitivity was analyzed through hypoxia/hypercapnia tests. ResultsPeakVO2 and VE/VCO2 slopes were 1.06±0.24l/min and 39.1±9.0, respectively. Throughout the exercise, 30% of VE was due to VD. VE/VCO2 slope significantly correlated with VD/VCO2 slope (r=0.82, p<0.001) but not with VA/VCO2 slope (r=0.3, p=ns). Peak exercise end-tidal CO2 (PetCO2) correlated with VD/VCO2 slope (r=−0.79, p<0.001) and VE/VCO2 slope (r=−0.91, p<0.001). Dead space(DS)/Tidal volume and P(arterial-et)CO2 were elevated without arterial hypoxemia suggesting a high VE/Q mismatch. Chemoreceptor peripheral response to hypoxia and central CO2 response were both enhanced being peripheral responses to hypoxia and hypercapnia 0.416±0.402 (normal ref values=0.285±0.221) l/min/O2Sat and 0.076±0.047 (0.066±0.430) l/min/mmHg, respectively; central hypercapnic chemosensitivity was 4.475±3.99 (2.352±0.936) l/min/mmHg. ConclusionsIncreased DS, VE/Q mismatch and chemorecptor response are among the main mechanisms involved in exercise hyperventilation in PH.ClinicalTrial.govNCT02892981

Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2 : role of carotid body CO2.

We asked if the type of carotid body (CB) chemoreceptor stimulus influenced the ventilatory gain of the central chemoreceptors to CO2 . The effect of CB normoxic hypocapnia, normocapnia and hypercapnia (carotid body PCO2 ≈ 22, 41 and 68 mmHg, respectively) on the ventilatory CO2 sensitivity of central chemoreceptors was studied in seven awake dogs with vascularly-isolated and extracorporeally-perfused CBs. Chemosensitivity with one CB was similar to that in intact dogs. In four CB-denervated dogs, absence of hyper-/hypoventilatory responses to CB perfusion with PCO2 of 19-75 mmHg confirmed separation of the perfused CB circulation from the brain. The group mean central CO2 response slopes were increased 303% for minute ventilation (V̇I)(P ≤ 0.01) and 251% for mean inspiratory flow rate (VT /TI ) (P ≤ 0.05) when the CB was hypercapnic vs. hypocapnic; central CO2 response slopes for tidal volume (VT ), breathing frequency (fb ) and rate of rise of the diaphragm EMG increased in 6 of 7 animals but the group mean changes did not reach statistical significance. Group mean central CO2 response slopes were also increased 237% for V̇I(P ≤ 0.01) and 249% for VT /TI (P ≤ 0.05) when the CB was normocapnic vs. hypocapnic, but no significant differences in any of the central ventilatory response indices were found between CB normocapnia and hypercapnia. These hyperadditive effects of CB hyper-/hypocapnia agree with previous findings using CB hyper-/hypoxia.We propose that hyperaddition is the dominant form of chemoreceptor interaction in quiet wakefulness when the chemosensory control system is intact, response gains physiological, and carotid body chemoreceptors are driven by a wide range of O2 and/or CO2 .

Response to the reply of J. Duffin to our letter entitled ‘Acetazolamide and cerebrovascular function at high altitude’

Response to the reply of J. Duffin to our letter entitled ‘Acetazolamide and cerebrovascular function at high altitude’

CO2 rebreathing model in COPD: blood-to-gas equilibration

Rebreathing in a closed system can be used to estimate mixed venous PCO2 (PvCO2) and cardiac output, but these estimates are affected by VA/Q heterogeneity. The purpose of this study was to validate a mathematical model of CO2 exchange during CO2 rebreathing in 29 patients with chronic obstructive pulmonary disease (COPD), with baseline arterial PCO2 (PaCO2) ranging from 28 to 60 mmHg. Rebreathing increased end-tidal PCO2 (PETCO2) by 20 mmHg over 2.2 min. This model employed baseline values for inspired (bag) PCO2, estimated PvCO2, distribution of ventilation and blood flow in one high VA/Q and one low VA/Q compartment, the ventilation increase and conservation of mass equations to simulate time courses of PICO2, PETCO2, PvCO2, and PaCO2. Measured PICO2 and PETCO2 during rebreathing differed by an average (SEM) of 1.4 (0.4) mmHg from simulated values. By end of rebreathing, predicted PvCO2 was lower than measured and predicted PaCO2, indicating gas to blood CO2 flux. Estimates of the ventilatory response to CO2, quantified as the slope (S) of the ventilation increase versus PETCO2, were inversely related to gas-to-blood PCO2 disequilibria due to VA/Q heterogeneity and buffer capacity (BC), but not airflow limitation. S may be corrected for these artifacts to restore S as a more valid noninvasive index of central CO2 responsiveness. We conclude that a rebreathing model incorporating baseline VA/Q heterogeneity and BC can simulate gas and blood PCO2 in patients with COPD, where VA/Q variations are large and variable.

Peripheral chemoreceptor insensitivity in chronic severe anaemia.

Ventilatory response to central and peripheral chemoreceptor stimulation by carbon dioxide was assessed in 15 severely and chronically anaemic subjects before and after the correction of anaemia. Whereas the central CO2 responsiveness was found to be normal in the anaemic state, the peripheral response to CO2 was remarkably depressed. This blunted peripheral response to CO2 was restored to normal with the correction of anaemia.

Assessment of responsiveness to carbon dioxide in patients with chronic airways obstruction by rate of isometric inspiratory pressure development.

1. Responsiveness to CO2 was measured in forty patients with chronic airways obstruction in terms of ventilation and rate of isometric inspiratory pressure change [(dP/dt)max]. 2. The ventilatory response was below the normal range in eighteen out of twenty-two patients with normal arterial CO2 tensions and in all of eighteen patients with CO2 retention. 2. The (dP/dt)max. response was distributed throughout the normal range in all but one of the patients with normal arterial CO2 tension. In all the patients with CO2 retention the (dP/dt)max. response was either at or below the lower limit of the normal range. 4. Although the ventilatory responses correlated significantly with FEV1 there was no such correlation for the (dP/dt)max. responses. 5. The (dP/dt)max. response showed a significant negative correlation with Pa,CO2. 6. It is believed that the (dP/dt)max. response to CO2 can be used to assess central CO2 responsiveness in subjects with airways obstruction independently of mechanical factors limiting their ventilation.