Impact Of Hypercapnia Research Articles

Acute Intermittent Hypoxia with Hypercapnia has Complex effects on Phrenic Long-Term Facilitation that Depend on Delivery in the Rest versus Active Phase in Rats

Exploration of mechanisms giving rise to respiratory motor plasticity, such as phrenic long-term facilitation (pLTF) following acute intermittent hypoxia (AIH), has inspired new therapeutic approaches to treat individuals affected by conditions such as spinal cord injury or other clinical disorders. One key step in the translation between rodent models and humans is the apparent need for hypercapnia (either baseline or within hypoxic episodes) during AIH. Whereas AIH consisting of 15, 1-minute hypoxic episodes (1-minute intervals) elicits robust pLTF in rats, similar protocols have minimal impact in humans—unless PaCO2 levels are increased. Although prior studies report that elevated baseline CO2 actually impairs AIH-induced pLTF in rats, the impact of hypercapnia within hypoxic episodes is not known. Thus, we compared AIH with and without concurrent hypercapnia (AIH versus AIHH) on pLTF in anesthetized rats. Since our laboratory recently reported profound time-of-day effects on pLTF magnitude and/or mechanisms, we also compared AIH versus AIHH-induced pLTF during the daily rest and active phase. We hypothesized that AIHH would enhance pLTF versus AIH in both phases, suggesting it may be a more effective intervention to elicit respiratory motor plasticity and respiratory rehabilitation. pLTF was assessed in anesthetized, paralyzed, vagotomized and ventilated male Sprague-Dawley rats ( n=6 per group) exposed to moderate AIH (arterial PO2 = 40-55mmHg) consisting of: 1) 15, 1-minute hypoxic episodes with concurrent hypercapnia (arterial PCO2 ~50mmHg) or 15, 1-minute episodes of isocapnic hypoxia (baseline arterial PCO2 ~2 mmHg above the recruitment threshold; ~40-42 mmHg). We also compared AIHH versus AIH during the active phase using prior published data (AIHH, n = 4; AIH, n = 7; data from Nair et al., Function, 2023 and Marciante et al., Function, 2023, respectively). Contrary to our hypothesis, pLTF was attenuated 90 minutes post-AIHH (37±8%) versus AIH (83±4%; p<0.001) in the rest phase. In striking contrast, during the active phase, pLTF was greater with AIHH (60±11%) versus AIH (30±4%; P=0.012). These unexpected outcomes demonstrate that time of day (or the rest/active phase) must be considered before adding hypercapnia to an AIH protocol. Although the mechanisms of this difference remain unclear, our results make clear that there is still a great deal to learn about mechanisms of AIH-induced respiratory motor plasticity, including the complex interplay between hypoxia, hypercapnia and their impact on pLTF. Supported by: NIH R01 HL147554 & R01 HL148030 (PI: G. Mitchell). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impact of Arterial CO2 Retention in Patients With Moderate or Severe ARDS.

Lung-protective ventilation (reduced tidal volume and limited plateau pressure) may lead to CO2 retention. Data about the impact of hypercapnia in patients with ARDS are scarce and conflicting. We performed a non-interventional cohort study with subjects with ARDS admitted from 2006 to 2021 and with PaO2 /FIO2 ≤ 150 mm Hg. We examined the association between severe hypercapnia (PaCO2 ≥ 50 mm Hg) on the first 5 days after the diagnosis of ARDS and death in ICU for 930 subjects. All the subjects received lung-protective ventilation. Severe hypercapnia was noted in 552 subjects (59%) on the first day of ARDS (day 1); 323/930 (34.7%) died in the ICU. Severe hypercapnia on day 1 was associated with mortality in the unadjusted (odds ratio 1.54, 95% CI 1.16-1.63; P = .003) and adjusted (odds ratio 1.47, 95% CI 1.08-2.43; P = .004) models. In the Bayesian analysis, the posterior probability that severe hypercapnia was associated with ICU death was > 90% in 4 different priors, including a septic prior for this association. Sustained severe hypercapnia on day 5, defined as severe hypercapnia present from day 1 to day 5, was noted in 93 subjects (12%). After propensity score matching, severe hypercapnia on day 5 remained associated with ICU mortality (odds ratio 1.73, 95% CI 1.02-2.97; P = .047). Severe hypercapnia was associated with mortality in subjects with ARDS who received lung-protective ventilation. Our results deserve further evaluation of the strategies and treatments that aim to control CO2 retention.

Hypercapnia and extracorporeal carbon dioxide removal (ECCO2R) in the acute respiratory distress syndrome

As a result of technical improvements, extracorporeal techniques for carbon dioxide removal have become an attractive option in managing adults with acute respiratory failure. However, evidence to support its use is scarce, and several questions regarding the best way to implement this therapy remain unanswered, which can be associated with severe side effects. In this review, we will present the currently available knowledge on (1) ECCO2R as an adjuvant treatment to invasive mechanical ventilation, (2) the impact of hypercapnia in patients with acute respiratory distress syndrome (ARDS), (3) the pathophysiological rationale and evidence of ECCO2R in patients with ARDS.

Cerebral oxidative metabolism is decreased with extreme apnoea in humans; impact of hypercapnia.

The present study describes the cerebral oxidative and non-oxidative metabolism in man during a prolonged apnoea (ranging from 3min36s to 7min26s) that generates extremely low levels of blood oxygen and high levels of carbon dioxide. The cerebral oxidative metabolism, measured from the product of cerebral blood flow and the radial artery-jugular venous oxygen content difference, was reduced by ∼29% at the termination of apnoea, although there was no change in the non-oxidative metabolism. A subset study with mild and severe hypercapnic breathing at the same level of hypoxia suggests that hypercapnia can partly explain the cerebral metabolic reduction near the apnoea breakpoint. A hypercapnia-induced oxygen-conserving response may protect the brain against severe oxygen deprivation associated with prolonged apnoea. Prolonged apnoea in humans is reflected in progressive hypoxaemia and hypercapnia. In the present study, we explore the cerebral metabolic responses under extreme hypoxia and hypercapnia associated with prolonged apnoea. We hypothesized that the cerebral metabolic rate for oxygen (CMRO2 ) will be reduced near the termination of apnoea, attributed in part to the hypercapnia. Fourteen elite apnoea-divers performed a maximal apnoea (range 3min 36s to 7min 26s) under dry laboratory conditions. In a subset study with the same divers, the impact of hypercapnia on cerebral metabolism was determined using varying levels of hypercapnic breathing, against the background of similar hypoxia. In both studies, the CMRO2 was calculated from the product of cerebral blood flow (ultrasound) and the radial artery-internal jugular venous oxygen content difference. Non-oxidative cerebral metabolism was calculated from the ratio of oxygen and carbohydrate (lactate and glucose) metabolism. The CMRO2 was reduced by ∼29% (P<0.01, Cohen's d=1.18) near the termination of apnoea compared to baseline, although non-oxidative metabolism remained unaltered. In the subset study, in similar backgrounds of hypoxia (arterial O2 tension: ∼38.4mmHg), severe hypercapnia (arterial CO2 tension: ∼58.7mmHg), but not mild-hypercapnia (arterial CO2 tension: ∼46.3mmHg), depressed the CMRO2 (∼17%, P=0.04, Cohen's d=0.87). Similarly to the apnoea, there was no change in the non-oxidative metabolism. These data indicate that hypercapnia can partly explain the reduction in CMRO2 near the apnoea breakpoint. This hypercapnic-induced oxygen conservation may protect the brain against severe hypoxaemia associated with prolonged apnoea.

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-α protein stability and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-α protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO2 Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-α protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-α subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated.

Cerebral oxygenation in mechanically ventilated early cardiac arrest survivors: The impact of hypercapnia

BackgroundOptimal cerebral oxygenation is considered fundamental to cerebral protection in cardiac arrest (CA) patients. Hypercapnia increases cerebral blood flow and may also improve cerebral oxygenation. It is uncertain, however, whether this effect occurs in mechanically ventilated early survivors of CA. MethodsWe enrolled mechanically ventilated resuscitated patients within 36h of their cardiac arrest. We performed a prospective double cross-over physiological study comparing the impact of normocapnia (PaCO2 35–45mmHg) vs. mild hypercapnia (PaCO2 45–55mmHg) on regional cerebral tissue oxygen saturation (SctO2) assessed by near infrared spectroscopy (NIRS). ResultsWe studied seven adult CA patients with a median time to return of spontaneous circulation of 28min at a median of 26h and 30min after CA. During normocapnia (median EtCO2 of 32mmHg [30–41mmHg] and PaCO2 of 37mmHg [32–45mmHg]) the median NIRS-derived left frontal SctO2 was 61% [52–65%] and the right frontal SctO2 was 61% [54–68%]. However, during mild hypercapnia (median EtCO2 of 49mmHg [40–57mmHg] and PaCO2 of 52mmHg [43–55mmHg) the median left frontal SctO2 increased to 69% [59–78%] and the right frontal SctO2 increased to 73% [61–76%])(p=0.001, for all comparisons). ConclusionDuring the early post-resuscitation period, in mechanically ventilated CA patients, mild hypercapnia increases cerebral oxygenation as assessed by NIRS. Further investigations of the effect of prolonged mild hypercapnia on cerebral oxygenation and patient outcomes appear justified.

Predicting the impact of ocean acidification on benthic biodiversity: What can animal physiology tell us?

For the past 200 years, the oceans have been absorbing carbon dioxide at an unprecidented rate. It is now evident that this ongoing process has already significantly altered seawater carbon chemistry at a global scale and will continue to do so for hundreds of years to come; a phenomenon termed “ocean acidification”. The challenge currently facing scientists is to predict the long term implications of ocean acidification for the diversity of marine organisms and for the ecosystem functions this diversity sustains. This challenge is all the more difficult considering that empirical data which specifically address the impact of ocean acidification on marine biodiversity are currently lacking. In the face of growing political and public pressure to provide answers, what predictions can be made and how reliable are the assumptions on which those predictions depend? Here we review the extent to which the few existing data, and understanding gained from previous physiological studies, can be used to make predictions for marine biodiversity. In doing so we also scrutinise some established paradigms concerning the impact of hypercapnia, resulting from seawater acidification, on marine organisms.

The impact of hypercapnia on retinal capillary blood flow assessed by scanning laser Doppler flowmetry

Aim: To determine the effect of hypercapnia on retinal capillary blood flow using scanning laser Doppler flowmetry (SLDF). Methods: One randomly selected eye of each of 10 normal healthy subjects (mean age 25 years, SD 2.3) was studied. Subjects breathed unrestricted air for 15 min before (baseline) and after raising fractional (percent) end-tidal concentration of CO 2 (F ETCO 2) for 15 min by adding low flows of CO 2 to air entering a sequential gas delivery circuit attached to a nasal mask. Five good quality baseline SLDF images were acquired both of the optic nerve head (ONH) and of the macula. Subsequently, a minimum of 7 sequential images were acquired during hypercapnia. Five further images were acquired of the ONH, or of the macula, after returning to unlimited air breathing. The respiratory parameters of subjects were continually monitored. Results: The group mean increase in end-tidal CO 2 was 14.13% (SD 4.10) relative to baseline. The nasal macula ( P = 0.028) and foveal ( P = 0.042) areas showed a significant increase in retinal capillary blood flow in response to hypercapnia while no significant change was noted in the ONH or temporal macula areas. Change in blood flow significantly correlated with change of F ETCO 2 and/or end-tidal PO 2 for 3 of the 4 locations. Conclusions: Hypercapnia provoked a significant increase in retinal capillary blood flow in 2 of 4 retinal locations. Hypercapnia also induced a change in respiratory parameters that significantly correlated with change in retinal capillary blood flow in 3 of the 4 locations.