Levels Of Hypercapnia Research Articles

Mild and moderate chronic hypercapnia elicit distinct transcriptomic responses of immune function in cardiorespiratory nuclei.

Chronic hypercapnia (CH) is a hallmark of respiratory-related diseases, and the level of hypercapnia can acutely or progressively become more severe. Previously, we have shown time-dependent adaptations in steady-state physiology during mild (arterial Pco2 ∼55 mmHg) and moderate (∼60 mmHg) CH in adult goats, including transient (mild CH) or sustained (moderate CH) suppression of acute chemosensitivity suggesting limitations in adaptive respiratory control mechanisms as the level of CH increases. Changes in specific markers of glutamate receptor plasticity, interleukin-1ß, and serotonergic modulation within key nodes of cardiorespiratory control do not fully account for the physiological adaptations to CH. Here, we used an unbiased approach (bulk tissue RNA sequencing) to test the hypothesis that mild or moderate CH elicits distinct gene expression profiles in important brain stem regions of cardiorespiratory control, which may explain the contrasting responses to CH. Gene expression profiles from the brain regions validated the accuracy of tissue biopsy methodology. Differential gene expression analyses revealed greater effects of CH on brain stem sites compared with the medial prefrontal cortex. Mild CH elicited an upregulation of predominantly immune-related genes and predicted activation of immune-related pathways and functions. In contrast, moderate CH broadly led to downregulation of genes and predicted inactivation of cellular pathways related to the immune response and vascular function. These data suggest that mild CH leads to a steady-state activation of neuroinflammatory pathways within the brain stem, whereas moderate CH drives the opposite response. Transcriptional shifts in immune-related functions may underlie the cardiorespiratory network's capability to respond to acute, more severe hypercapnia when in a state of progressively increased CH.NEW & NOTEWORTHY Mild chronic hypercapnia (CH) broadly upregulated immune-related genes and a predicted activation of biological pathways related to immune cell activity and the overall immune response. In contrast, moderate CH primarily downregulated genes related to major histocompatibility complex signaling and vasculature function that led to a predicted inactivation of pathways involving the immune response and vascular endothelial function. The severity-dependent effect on immune responses suggests that neuroinflammation has an important role in CH and may be important in the maintenance of proper ventilatory responses to acute and chronic hypercapnia.

Hemodynamic and oxygen-metabolic responses of the awake mouse brain to hypercapnia revealed by multi-parametric photoacoustic microscopy

A widely used cerebrovascular stimulus and common pathophysiologic condition, hypercapnia is of great interest in brain research. However, it remains controversial how hypercapnia affects brain hemodynamics and energy metabolism. By using multi-parametric photoacoustic microscopy, the multifaceted responses of the awake mouse brain to different levels of hypercapnia are investigated. Our results show significant and vessel type-dependent increases of the vessel diameter and blood flow in response to the hypercapnic challenges, along with a decrease in oxygen extraction fraction due to elevated venous blood oxygenation. Interestingly, the increased blood flow and decreased oxygen extraction are not commensurate with each other, which leads to reduced cerebral oxygen metabolism. Further, time-lapse imaging over 2-hour chronic hypercapnic challenges reveals that the structural, functional, and metabolic changes induced by severe hypercapnia (10% CO2) are not only more pronounced but more enduring than those induced by mild hypercapnia (5% CO2), indicating that the extent of brain’s compensatory response to chronic hypercapnia is inversely related to the severity of the challenge. Offering quantitative, dynamic, and CO2 level-dependent insights into the hemodynamic and metabolic responses of the brain to hypercapnia, these findings might provide useful guidance to the application of hypercapnia in brain research.

Decapneization as supportive therapy for the treatment of status asthmaticus: a case report

BackgroundAcute severe asthma is a life-threatening medical emergency. Characteristics of asthma include increased airway resistance and dynamic pulmonary hyperinflation that can manifest in dangerous levels of hypercapnia and acidosis, with significant mortality and morbidity. Severe respiratory distress can lead to endotracheal intubation followed by mechanical ventilation, which can cause increased air trapping with dynamic hyperinflation, predisposing the lungs to barotraumas.Case presentationThe present case report describes the use of the minimally invasive ECCO2R ProLUNG® (Estor) with protective low-tidal-volume ventilation, in a Caucasian patient with near-fatal asthma and with no response to conventional therapy.ConclusionsSince hypercarbia rather than hypoxemia is the primary abnormality in status asthmaticus, a rescue therapeutic strategy combining the ECCO2R membrane ProLUNG® (Estor) with ultra-protective low-tidal-volume ventilation can be successfully applied to limit the risk of severe barotrauma during invasive mechanical ventilation. ECCO2R ProLUNG® is a partial respiratory support technique that, based on the use of an extracorporeal circuit with a gas-exchange membrane, achieves relevant CO2 clearance directly from the blood using double-lumen venous-venous vascular access, at blood flow in the range of 0.4–1.0 L/minute.

Sex Differences in the Cerebral Hemodynamic Response to Hypercapnia in Young Adults

Despite sexual dimorphism present in stroke and risk for Alzheimer’s disease, sex differences in cerebral blood flow regulation remain controversial. Discrepancies in the literature may be due to menstrual cycle control as well as the inherent difficulty of quantifying cerebral blood flow in humans. The purpose of this study was to evaluate the cerebral hemodynamic response to hypercapnia in young men and premenopausal women using two approaches: 1) transcranial Doppler ultrasound (TCD); and 2) 4D flow MRI. Twenty habitually physically active participants including young men (YM; n = 10, age = 24±2 y) and young women (YW; n = 10, age = 26±4 y) were studied. Young women were studied during days 2–6 of the menstrual cycle. During separate, randomized study visits, left middle cerebral artery (LMCA) velocity was measured with TCD and LMCA flow was measured with 4D flow MRI during normocapnia and two levels of hypercapnia (4% and 6% CO2). 4D flow MRI quantifies cerebral hemodynamic and angiographic data simultaneously. End‐tidal carbon dioxide and mean arterial pressure were continuously monitored with an anesthesia monitor. At baseline, LMCA velocity (YM: 53±3 cm/s vs. YW: 60±4 cm/s, p=0.15) and LMCA flow (YM: 121±10 ml/min vs. YW: 131±6 ml/min, p=0.41) were not significantly different between groups. There was a trend for YM to demonstrate a larger LMCA cross‐sectional area compared with YW at baseline (YM: 0.071±0.002 cm2 vs. YW: 0.065±0.002 cm2, p=0.052). In response to hypercapnia, the LMCA velocity response was not different between groups (YM: 1.17±0.29 cm/s/mmHg vs. YW: 1.24±0.17 cm/s/mmHg, p=0.83). However, YM demonstrated a greater LMCA flow response compared with YW (YM: 2.98±0.40 ml/min/mmHg vs. YW: 1.38±0.26 ml/min/mmHg, p<0.01), even when accounting for changes in blood pressure. In addition, the LMCA significantly vasodilated in YM in response to hypercapnia (p<0.05); however, there was no significant change in LMCA cross‐sectional area in response to hypercapnia in YW (p=0.13). These results suggest that young men have augmented cerebral blood flow response to hypercapnia compared with young women. In addition, due to small changes in vessel cross‐sectional area during hypercapnia, sex differences may be underestimated if cerebral blood velocity is used as a surrogate of blood flow.Support or Funding InformationSupported by the Wisconsin Alumni Research Foundation and the National Institutes of Health T32 HL‐007936.

Hypercapnia augments resistive exercise-induced elevations in intraocular pressure in older individuals.

What is the central question of this study? Astronauts on-board the International Space Station (ISS) perform daily exercises designed to prevent muscle atrophy and bone demineralization: what is the effect of resistive exercise performed by subjects while exposed to the same level of hypercapnia as on the ISS on intraocular pressure (IOP)? What is the main finding and its importance? The static exercise-induced elevation in IOP during 6° prone head-down tilt (simulating the headward shift of body fluids in microgravity) is augmented by hypercapnia and exceeds the ocular hypertension threshold. The present study assessed the effect of 6° head-down (establishing the cephalad fluid displacement noted in astronauts in microgravity) prone (simulating the effect on the eye) tilt during rest and exercise (simulating exercise performed by astronauts to mitigate the sarcopenia induced by unloading of weight-bearing limbs), in normocapnic and hypercapnic conditions (the latter simulating conditions on the International Space Station) on intraocular pressure (IOP). Volunteers (mean age=57.8±6 years, n=10) participated in two experimental sessions, each comprising: (i) 10min rest, (ii) 3min static handgrip exercise (30% max), and (iii) 2min recovery, inspiring either room air (NCAP) or a hypercapnic mixture (1% CO2 , HCAP). We measured IOP in the right eye, cardiac output (CO), stroke volume (SV), heart rate (HR) and mean arterial pressure (MAP) at regular intervals. Baseline IOP in the upright seated position while breathing room air was 14.1±2.9mmHg. Prone 6° head-down tilt significantly (P<0.01) elevated IOP in all three phases of the NCAP (rest: 27.0±3.7mmHg; exercise: 32.2±4.8mmHg; recovery: 27.4±4.0mmHg) and HCAP (rest: 27.3±4.3mmHg; exercise: 34.2±6.0mmHg; recovery: 29.1±5.8mmHg) trials, with hypercapnia augmenting the exercise-induced elevation in IOP (P<0.01). CO, SV, HR and MAP were significantly increased during handgrip dynamometry, but there was no effect of hypercapnia. The observed IOP measured during prone 6° HDT in all phases of the NCAP and HCAP trials exceeded the threshold pressure defining ocular hypertension. The exercise-induced increase in IOP is exacerbated by hypercapnia.

Hyperoxia blunts renal sympathetic nerve activity response to acute intermittent hypercapnia in rats.

Activation of the sympathetic nervous system plays an important role in the pathophysiology of sleep-related breathing disorders. The aim of the present study was to examine the effects of different levels of hypercapnia in the presence of various background oxygen levels on the magnitude of sympathoexcitation, measured by the renal sympathetic nerve activity (RSNA) in the acute intermittent hypercapnia (AIHc) rat model. The study was conducted on 56 urethane-anesthetized, vagotomized and mechanically ventilated Sprague-Dawley rats (n = 7/group). Each experimental group was subjected to a distinct AIHc protocol that varied in the applied levels of hypercapnia and background oxygen. Mean arterial pressure and RSNA were analyzed in 7 experimental time points: baseline, five hypercapnic episodes (each lasting 3 min) and 15 minutes following the last hypercapnic episode. Exposure to severe hypercapnia (FiCO2 = 0.15) evoked an increase in RSNA, which was preserved throughout the protocol, whereas in moderate hypercapnia (FiCO2 = 0.05) groups there was a trend of progressive diminution of RSNA magnitude following the first hypercapnic episode. Exposure to severe hypercapnia elicited significantly greater RSNA response during first hypercapnic episode and it was enhanced during subsequent episodes compared to exposure to moderate hypercapnia. Additionally, hyperoxic2 background (50% O2) blunted the RSNA response to AIHc compared to room air background, both in severe and moderate hypercapnia groups. Mean arterial blood pressure was preserved throughout the experimental protocol in all studied groups. These findings indicate that acute intermittent hypercapnia evokes increased renal sympathetic nerve activity that is dependent on the severity of hypercapnic exposures and the background oxygen level.

The voxel-wise analysis of false negative fMRI activation in regions of provoked impaired cerebrovascular reactivity.

Task-evoked Blood-oxygenation-level-dependent (BOLD-fMRI) signal activation is widely used to interrogate eloquence of brain areas. However, data interpretation can be improved, especially in regions with absent BOLD-fMRI signal activation. Absent BOLD-fMRI signal activation may actually represent false-negative activation due to impaired cerebrovascular reactivity (BOLD-CVR) of the vascular bed. The relationship between impaired BOLD-CVR and BOLD-fMRI signal activation may be better studied in healthy subjects where neurovascular coupling is known to be intact. Using a model-based prospective end-tidal carbon dioxide (CO2) targeting algorithm, we performed two controlled 3 tesla BOLD-CVR studies on 17 healthy subjects: 1: at the subjects’ individual resting end-tidal CO2 baseline. 2: Around +6.0 mmHg CO2 above the subjects’ individual resting baseline. Two BOLD-fMRI finger-tapping experiments were performed at similar normo- and hypercapnic levels. Relative BOLD fMRI signal activation and t-values were calculated for BOLD-CVR and BOLD-fMRI data. For each component of the cerebral motor-network (precentral gyrus, postcentral gyrus, supplementary motor area, cerebellum und fronto-operculum), the correlation between BOLD-CVR and BOLD-fMRI signal changes and t-values was investigated. Finally, a voxel-wise quantitative analysis of the impact of BOLD-CVR on BOLD-fMRI was performed. For the motor-network, the linear correlation coefficient between BOLD-CVR and BOLD-fMRI t-values were significant (p<0.01) and in the range 0.33–0.55, similar to the correlations between the CVR and fMRI Δ%signal (p<0.05; range 0.34–0.60). The linear relationship between CVR and fMRI is challenged by our voxel-wise analysis of Δ%signal and t-value change between normo- and hypercapnia. Our main finding is that BOLD fMRI signal activation maps are markedly dampened in the presence of impaired BOLD-CVR and highlights the importance of a complementary BOLD-CVR assessment in addition to a task-evoked BOLD fMRI to identify brain areas at risk for false-negative BOLD-fMRI signal activation.

Sensitivity of the human ventilatory response to muscle metaboreflex activation during concurrent mild hypercapnia.

What is the central question of this study? What is the relationship between the level of systemic hypercapnia and the magnitude of the additional hyperpnoea produced in response to a standardized level of muscle metaboreflex activation? What is the main finding and its importance? When a standardized activation of the muscle metaboreflex was combined with exposure to increasing levels of hypercapnia, the hyperpnoea this caused increased linearly. The concept of a synergistic interaction between the muscle metaboreflex and the central chemoreflex in humans is supported by this finding. Ventilation increases during muscle metaboreflex activation when postexercise circulatory occlusion (PECO) traps metabolites in resting human muscle, but only in conditions of concurrent systemic hypercapnia. We hypothesize that a linear relationship exists between the level of hypercapnia and the magnitude of the additional hyperpnoea produced in response to a standardized level of muscle metaboreflex activation. Fifteen male subjects performed four trials, in which the end-tidal partial pressure of carbon dioxide ( ) was elevated by 1, 3, 7 or 10mmHg above resting values using a dynamic end-tidal forcing system. In each trial, subjects were seated in an isometric dynamometer designed to measure ankle plantar flexor force. Rest for 2 min in room air was followed by 15min of exposure to one of the four levels ofhypercapnia, at which 5min further rest was followed by 2 min of sustained isometric calf muscle contraction at 50% of predetermined maximal voluntary strength. Immediately before cessation of exercise, a cuff around the upper leg was inflated to a suprasystolic pressure to cause PECO for 3min, before its deflation and a further 5min of rest, concluding exposure to hypercapnia. The PECO consistently elevated mean arterial blood pressure by ∼10mmHg in all trials, indicating similar levels of metaboreflex activation. Increased ventilation during PECO was related to as described by the following linear regression equation: Change in minute ventilation (lmin-1 )=0.85× (mmHg)+0.80 (lmin-1 ). This finding supports our hypothesis and furthers the idea of a synergistic interaction between muscle metaboreflex activation and central chemoreflex stimulation.

Respiratory gas levels interact to control ventilatory motor patterns in isolated locust ganglia.

Large insects actively ventilate their tracheal system even at rest, using abdominal pumping movements, which are controlled by a central pattern generator (CPG) in the thoracic ganglia. We studied the effects of respiratory gases on the ventilatory rhythm by isolating the thoracic ganglia and perfusing its main tracheae with various respiratory gas mixtures. Fictive ventilation activity was recorded from motor nerves controlling spiracular and abdominal ventilatory muscles. Both hypoxia and hypercapnia increased the ventilation rate, with the latter being much more potent. Sub-threshold hypoxic and hypercapnic levels were still able to modulate the rhythm as a result of interactions between the effects of the two respiratory gases. Additionally, changing the oxygen levels in the bathing saline affected ventilation rate, suggesting a modulatory role for haemolymph oxygen. Central sensing of both respiratory gases as well as interactions of their effects on the motor output of the ventilatory CPG reported here indicate convergent evolution of respiratory control among terrestrial animals of distant taxa.

The Clinical Implications of Carbon Dioxide Increased Level in Arterial Blood Related to Severe Exacerbations of Chronic Obstructive Pulmonary Disease

In the evolution of patients with chronic obstructive pulmonary disease (COPD), exacerbations occur, especially, in severe stages, determining aggravated respiratory failure and decreased survival. In order to evaluate the implications of COPD exacerbations in patients with second type of chronic respiratory failure and hypercapnic encephalopathy, a prospective observational study was done among 195 COPD in patients of Targu Mures Clinical County Hospital, Romania. Inclusion criteria consisted in severe exacerbations of COPD, complicated by hypercapnia, defined by an increased level of arterial blood gas carbon dioxide (PaCO2) �45 mmHg, suggestive for the second type of respiratory failure. The increased values of PaCO2 ranged between 45 and 112 mmHg among 95 patients. The prevalence of hypercapnia in COPD patients, admitted in hospital for severe exacerbations, was high (n=91/195; 46.66%). The majority of COPD patients (93.4%) were initially hospitalized in the intensive care unit (ICU) department because of hypercapnic encephalopathy. The mortality rate was higher among patients with endotracheal tube insertion than in patients treated by noninvasive mechanical ventilation. High levels of hypercapnia, conscience disorders and respiratory acidosis may be considered factors of severity in COPD exacerbation.

Native and exotic oysters in Brazil: Comparative tolerance to hypercapnia

Environmental hypercapnia in shallow coastal marine ecosystems can be exacerbated by increasing levels of atmospheric CO2. In these ecosystems organisms are expected to become increasingly subjected to pCO2 levels several times higher than those inhabiting ocean waters (e.g.: 10,000µatm), but still our current understanding on different species capacity to respond to such levels of hypercapnia is limited. Oysters are among the most important foundation species inhabiting these coastal ecosystems, although natural oyster banks are increasingly threatened worldwide. In the present study we studied the effects of hypercapnia on two important oyster species, the pacific oyster C. gigas and the mangrove oyster C. brasiliana, to bring new insights on different species response mechanisms towards three hypercapnic levels (ca. 1,000; 4,000; 10,000 µatm), by study of a set of biomarkers related to metabolic potential (electron transport system - ETS), antioxidant capacity (SOD, CAT, GSH), cellular damage (LPO) and energetic fitness (GLY), in two life stages (juvenile and adult) after 28 days of exposure.Results showed marked differences between each species tolerance capacity to hypercapnia, with contrasting metabolic readjustment strategies (ETS), different antioxidant response capacities (SOD, CAT, GSH), which generally allowed to prevent increased cellular damage (LPO) and energetic impairment (GLY) in both species. Juveniles were more responsive to hypercapnia stress in both congeners, and are likely to be most sensitive to extreme hypercapnia in the environment. Juvenile C. gigas presented more pronounced biochemical alterations at intermediate hypercapnia (4,000µatm) than C. brasiliana. Adult C. gigas showed biochemical alterations mostly in response to high hypercapnia (10,000µatm), while adult C. brasiliana were less responsive to this environmental stressor, despite presenting decreased metabolic potential.Our data bring new insights on the biochemical performance of two important oyster species, and suggest that the duration of extreme hypercapnia events in the ecosystem may pose increased challenges for these organisms as their tolerance capacity may be time limited.

Role of bronchodilation and pattern of breathing in increasing tidal expiratory flow with progressive induced hypercapnia in chronic obstructive pulmonary disease.

Hypercapnia (HC) in vitro relaxes airway smooth muscle; in vivo, it increases respiratory effort, tidal expiratory flows (V̇exp), and, by decreasing inspiratory duration (Ti), increases elastic recoil pressure (Pel) via lung viscoelasticity; however, its effect on airway resistance is uncertain. We examined the contributions of bronchodilation, Ti, and expiratory effort to increasing V̇exp with progressive HC in 10 subjects with chronic obstructive pulmonary disease (COPD): mean forced expiratory volume in 1 s (FEV1) 53% predicted. Lung volumes (Vl), V̇exp, esophageal pressure (Pes), Ti, and end-tidal Pco2 ([Formula: see text]) were measured during six tidal breaths followed by an inspiratory capacity (IC), breathing air, and at three levels of HC. V̇exp and V̇ with submaximal forced vital capacities breathing air (V̇sFVC) were compared. Pulmonary resistance ( Rl) was measured from the Pes-V̇ relationship. V̇exp and Pes at end-expiratory lung volume (EELV) + 0.3 tidal volume [V̇(0.3Vt) and Pes(0.3Vt), respectively], Ti, and Rl correlated with [Formula: see text] ( P < 0.001 for all) and were independent of tiotropium. [Formula: see text], Ti, and Pes(0.3Vt) predicted the increasing V̇(0.3Vt)/V̇sFVC(0.3Vt) [multiple regression analysis (MRA): P = 0.001, 0.004, and 0.025, respectively]. At [Formula: see text] ≥ 50 Torr, V̇(0.3Vt)/V̇sFVC(0.3Vt) exceeded unity in 30 of 36 measurements and was predicted by [Formula: see text] and Pes(0.3Vt) (MRA: P = 0.02 and 0.025, respectively). Rl decreased at [Formula: see text] 45 Torr ( P < 0.05) and did not change with further HC. IC and Vl(0.3Vt) did not change with HC. We conclude that in COPD HC increases V̇exp due to bronchodilation, increased Pel secondary to decreasing Ti, and increased expiratory effort, all promoting lung emptying and a stable EELV. NEW & NOTEWORTHY The response of airways to intrapulmonary hypercapnia (HC) is uncertain. In chronic obstructive pulmonary disease (COPD), progressive HC increases tidal expiratory flows by inducing bronchodilation and via an increased rate of inspiration and lung viscoelasticity, a probable increase in lung elastic recoil pressure, both changes increasing expiratory flows, promoting lung emptying and a stable end-expiratory volume. Bronchodilation with HC occurred despite optimal standard bronchodilator therapy, suggesting that in COPD further bronchodilation is possible.

Effects of Hypercapnia on Myocardial Blood Flow in Healthy Human Subjects.

Elevation of the end-tidal partial pressure of CO2 (PETco2) increases cerebral and myocardial blood flow (MBF), suggesting that it may be a suitable alternative to pharmacologic stress or exercise for myocardial perfusion imaging. The purpose of this study was to document the pharmacodynamics of CO2 for MBF using prospective end-tidal targeting to precisely control arterial Pco2 and PET to measure the outcome variable, MBF. Methods: Ten healthy men underwent serial 82Rb PET/CT imaging. Imaging was performed at rest and during 6-min hypercapnic plateaus (baseline; PETco2 at 50, 55, and 60 mm Hg; repeat of PETco2 at 60 mm Hg; and repeat of baseline). MBF was measured using 82Rb injected 3 min after the beginning of hypercapnia and a 1-tissue-compartment model with flow-dependent extraction correction. Results were compared with those obtained during an adenosine stress test (140 μg/kg/min). Results: Baseline PETco2 was 38.9 ± 0.8 (mean ± SD) mm Hg (range, 35-43 mm Hg). All PETco2 targets were sustained, with SDs of less than 1.5 mm Hg. Heart rate, systolic blood pressure, rate × pressure product, and respiratory frequency increased with progressive hypercapnia. MBF increased significantly at each level of hypercapnia to 1.92-fold over baseline (0.86 ± 0.24 vs. 0.45 ± 0.08 mL/min/g; P = 0.002) at a PETco2 of 60 mm Hg. MBF after the administration of adenosine was significantly greater than that with the maximal hypercapnic stimulus (2.00 vs. 0.86 mL/min/g; P < 0.0001). Conclusion: To our knowledge, this study is the first to assess the response of MBF to different levels of hypercapnia in healthy humans with PET. MBF increased with increasing levels of hypercapnia; MBF at a PETco2 of 60 mm Hg was double that at baseline.

Graded Hypercapnia-Calibrated BOLD: Beyond the Iso-metabolic Hypercapnic Assumption

Calibrated BOLD is a promising technique that overcomes the sensitivity of conventional fMRI to the cerebrovascular state; measuring either the basal level, or the task-induced response of cerebral metabolic rate of oxygen consumption (CMRO2). The calibrated BOLD method is susceptible to errors in the measurement of the calibration parameter M, the theoretical BOLD signal change that would occur if all deoxygenated hemoglobin were removed. The original and most popular method for measuring M uses hypercapnia (an increase in arterial CO2), making the assumption that it does not affect CMRO2. This assumption has since been challenged and recent studies have used a corrective term, based on literature values of a reduction in basal CMRO2 with hypercapnia. This is not ideal, as this value may vary across subjects and regions of the brain, and will depend on the level of hypercapnia achieved. Here we propose a new approach, using a graded hypercapnia design and the assumption that CMRO2 changes linearly with hypercapnia level, such that we can measure M without assuming prior knowledge of the scale of CMRO2 change. Through use of a graded hypercapnia gas challenge, we are able to remove the bias caused by a reduction in basal CMRO2 during hypercapnia, whilst simultaneously calculating the dose-wise CMRO2 change with hypercapnia. When compared with assuming no change in CMRO2, this approach resulted in significantly lower M-values in both visual and motor cortices, arising from significant dose-dependent hypercapnia reductions in basal CMRO2 of 1.5 ± 0.6%/mmHg (visual) and 1.8 ± 0.7%/mmHg (motor), where mmHg is the unit change in end-tidal CO2 level. Variability in the basal CMRO2 response to hypercapnia, due to experimental differences and inter-subject variability, is accounted for in this approach, unlike previous correction approaches, which use literature values. By incorporating measurement of, and correction for, the reduction in basal CMRO2 during hypercapnia in the measurement of M-values, application of our approach will correct for an overestimation in both CMRO2 task-response values and absolute CMRO2.

The long road to steady state in gas exchange: metabolic and ventilatory responses to hypercapnia and hypoxia in Cuvier's dwarf caiman.

Animals with intermittent lung ventilation and those exposed to hypoxia and hypercapnia will experience fluctuations in the bodily O2 and CO2 stores, but the magnitude and duration of these changes are not well understood amongst ectotherms. Using the changes in the respiratory exchange ratio (RER; CO2 excretion divided by O2 uptake) as a proxy for changes in bodily gas stores, we quantified time constants in response to hypoxia and hypercapnia in Cuvier's dwarf caiman. We confirm distinct and prolonged changes in RER during and after exposure to hypoxia or hypercapnia. Gas exchange transients were evaluated in reference to predictions from a two-compartment model of CO2 exchange to quantify the effects of the levels of hypoxia and hypercapnia, duration of hypercapnia (30-300 min) and body temperature (23 versus 33°C). For hypercapnia, the transients could be adequately fitted by two-phase exponential functions, and slow time constants (after 300 min hypercapnia) concurred reasonably well with modelling predictions. The slow time constants for the decays after hypercapnia were not affected by the level of hypercapnia, but they increased (especially at 23°C) with exposure time, possibly indicating a temporal and slow recruitment of tissues for CO2 storage. In contrast to modelling predictions, elevated body temperature did not reduce the time constants, probably reflecting similar ventilation rates in transients at 23 and 33°C. Our study reveals that attainment of steady state for gas exchange requires considerable time and this has important implications for designing experimental protocols when studying ventilatory control and conducting respirometry.

Permissive hypercapnia: Is there any upper limit?

Sir, We read the article by Garg SK “Permissive hypercapnia: Is there any upper limit?”[1] with great interest. The author has rightly focused on a current protective lung ventilation strategy. Though there are several reports of extreme levels of hypercapnia tolerated by patients no safe upper limit has been described. We would like to add following facts. Permissive hypercapnia allows for low-tidal volume ventilation and hence minimizes ventilator associated lung injury. It also reduces inflammatory response in lungs by attenuating free radical formation, nuclear factor kappa-β activation and increased tumor necrosis factor-β, interleukin-1, 6, 8 production. On the contrary, it impairs plasma membrane wound healing in injured lungs in a pH dependent fashion[2] and also prevents alveolar fluid resorption by inhibiting Na-K ATPase of alveolar epithelial cells. Sustained hypercapnia in cases of pulmonary infection increases bacterial load and may further aggravate lung injury. Hence in conditions of sepsis associated lung injury permissive hypercarbia would be beneficial. Elevated CO2 level also induces mitochondrial dysfunction and impairs alveolar epithelial cell proliferation. Hypercapnic acidosis increases ventilatory drive and if patient is not properly sedated and paralyzed, patient-ventilator dyssynchrony may occur and result in increased transpulmonary pressure. Previous animal studies have reported vasogenic cerebral edema in hypercapnic acidosis and in human beings cerebral edema have been reported in severe respiratory acidosis associated with asthma.[3] Hypercapnia has a beneficial effect on brain in an optimal range. Lowering CO2 causes cerebral vasoconstriction whereas increased CO2 results in cerebral edema. Hence, like any other drug “permissive hypercapnia” should be used judiciously and under strict hemodynamic monitoring. Hypotension in this patient may not be attributed to hypercapnic acidosis. Though hypercapnic acidosis has a negative inotropic effect it increases net cardiac output by sympatho-adrenal stimulation and reduction in systemic vascular resistance.[4] Usually hypercapnic metabolic acidosis doesn't require buffering as it has less effect on the cardiovascular system. In situations where hemodynamic compromise occurs buffering should ideally be done by tris-hydroxy-amino-methane (THAM/Tromethamine), as it does not release CO2 and more effective in the correction of pH. Weber et al. have also found that THAM attenuates the reversible myocardial depressant action of permissive hypercapnia in patients with acute respiratory distress syndrome.[5] Last but not the least, it is not clear from the case whether the author tried recruitment maneuvers or how did they achieve optimum positive end-expiratory pressure as a strategy for open lung ventilation and preventing atelectrauma. Moreover, managing elevated PaCO2 by increasing tidal volume is now known to be unacceptable; however, management by increasing the respiratory rate, although common is of uncertain impact. For example, increasing respiratory rate frequency from 17 to 35/min adds over 25,000 additional opening and closing cycles per day to an already injured lung, and laboratory data suggest that this approach is associated with additional lung injury.[6]

Contributions of KATP and KCa channels to cerebral arteriolar dilation to hypercapnia in neonatal brain.

Mechanisms by which Pco2 controls cerebral vascular tone remain uncertain. We hypothesize that potassium channel activation contributes to the neonatal cerebrovascular dilation in response to increases in Paco2. To test this hypothesis, experiments were performed on newborn pigs with surgically implanted, closed cranial windows. Hypercapnia was induced by ventilation with elevated Pco2 gas in the absence and presence of the KATP channel inhibitor, glibenclamide and/or the KCa channel inhibitor, paxillin. Dilations to pinacidil, a selective KATP channel activator, without and with glibenclamide, were used to evaluate the efficacy of KATP channel inhibition. Dilations to NS1619, a selective KCa channel activator, without and with paxillin, were used to evaluate the efficacy of KCa channel inhibition. Cerebrovascular responses to the KATP and KCa channel activators, pinacidil and NS1619, respectively, cAMP‐dependent dilator, isoproterenol, and cGMP‐dependent dilator, sodium nitroprusside (SNP), were used to evaluate the selectivity of glibenclamide and paxillin. Glibenclamide blocked dilation to pinacidil, but did not inhibit dilations to NS1619, isoproterenol, or SNP. Glibenclamide prior to hypercapnia decreased mean pial arteriole dilation ~60%. Glibenclamide treatment during hypercapnia constricted arterioles ~35%. The level of hypercapnia, Paco2 between 50 and 75 mmHg, did not appear to be involved in efficacy of glibenclamide in blocking dilation to Paco2. Similarly to glibenclamide and KATP channel inhibition, paxillin blocked dilation to the KCa channel agonist, NS1619, and attenuated, but did not block, arteriolar dilation to hypercapnia. Treatment with both glibenclamide and paxillin abolished dilation to hypercapnia. Therefore, either glibenclamide or paxillin that block dilation to their channel agonists, pinacidil or NS1619, respectively, only partially inhibit dilation to hypercapnia. Block of both KATP and KCa channels completely prevent dilation hypercapnia. These data suggest hypercapnia activates both KATP and KCa channels leading to cerebral arteriolar dilation in newborn pigs.

Aminophylline increases respiratory muscle activity during hypercapnia in humans

BackgroundTheophylline is an old drug traditionally used as a bronchodilator, although it was recently shown to possess anti-inflammatory properties, enhance the actions of corticosteroid actions, and stimulate the respiratory neuronal network. Theophylline has been recognized as an important drug for not only asthma but also corticosteroid-insensitive chronic obstructive pulmonary disease (COPD). To clarify the role of theophylline in hypercapnic ventilatory responses in humans, we analyzed the effects of aminophylline administered at the usual clinical therapeutic doses on ventilation and augmentation of respiratory muscle contractility in room air and under 3 conditions of hypercapnia. Study designWe performed electromyography (EMG) of the parasternal intercostal muscle (PARA) and transversus abdominis muscle (TA) in 7 healthy subjects and recorded both ventilatory parameters and EMG data in room air and under 3 conditions of hypercapnia before (control) and during aminophylline administration. ResultsBefore aminophylline administration (control), hypercapnic stimulation elicited ventilatory augmentation in a hypercapnia intensity-dependent manner. Ventilatory parameters (tidal volume, frequency of respiration, and minute ventilation) showed significant increases from lower PaCO2 levels during aminophylline administration when compared with the corresponding values before aminophylline administration. EMG activity of both PARA and TA increased significantly at each level of hypercapnia, and those augmentations were shown from lower PaCO2 levels during aminophylline administration. ConclusionAminophylline administered at the usual clinical therapeutic dose increases ventilation and EMG activity of both inspiratory and expiratory muscles during hypercapnia in healthy humans.

Permissive hypercapnia: From the ICU to the operating room

Although the effect of permissive hypercapnia on hemodynamics and right ventricular function was previously reported in patients with acute respiratory distress syndrome, the effects of acute controlled hypercapnia on right ventricular function during one-lung ventilation have not yet been investigated systematically. Experimental evidence is conflicting concerning the pulmonary vasodilatory or vasoconstrictive effect of hypercapnic acidosis. The final effect of hypercapnic acidosis on physiological functions depends on the level of hypercapnia and the context of the individual (healthy vs. diseased).

Nocturnal noninvasive positive pressure ventilation in stable COPD: A systematic review and individual patient data meta-analysis

The effects of nocturnal noninvasive positive pressure ventilation (NIPPV) in patients with stable chronic obstructive pulmonary disease (COPD) remain controversial. The Cochrane Airways group Register of Trials, MEDLINE, EMBASE and CINAHL were searched up to August 2012. Individual patient data from randomised controlled trials on NIPPV outcomes were selected for two separate meta-analyses: the first with follow-up of 3 months and the second with 12 months of follow-up. Additionally, subgroup analyses within the NIPPV group comparing IPAP levels, compliance and levels of hypercapnia on change in PaCO2 after 3 months were performed. Seven trials (245 patients) were included. All studies were considered of moderate to high quality. No significant difference was found between NIPPV and control groups after 3 or 12 months of follow-up when looking at PaCO2 and PaO2, 6-minute walking distance, health-related quality-of-life, forced expiratory volume in 1s, forced vital capacity, maximal inspiratory pressure and sleep efficiency. Significant differences in change in PaCO2 after 3 months were found for patients ventilated with IPAP levels of at least 18cm H2O, for patients who used NIPPV for at least 5hper night as well as for patients with baseline PaCO2 of at least 55mmHg when compared to patients with lower IPAP levels, poorer compliance or lower levels of hypercapnia. At present, there is insufficient evidence to support the application of routine NIPPV in patients with stable COPD. However, higher IPAP levels, better compliance and higher baseline PaCO2 seem to improve PaCO2.