Mechanisms and Consequences of Oxygen and Carbon Dioxide Sensing in Mammals.

Molecular oxygen (O2) and carbon dioxide (CO2) are the primary gaseous substrate and product of oxidative phosphorylation in respiring organisms, respectively. Variance in the levels of either of these gasses outside of the physiological range presents a serious threat to cell, tissue, and organism survival. Therefore, it is essential that endogenous levels are monitored and kept at appropriate concentrations to maintain a state of homeostasis. Higher organisms such as mammals have evolved mechanisms to sense O2 and CO2 both in the circulation and in individual cells and elicit appropriate corrective responses to promote adaptation to commonly encountered conditions such as hypoxia and hypercapnia. These can be acute and transient nontranscriptional responses, which typically occur at the level of whole animal physiology or more sustained transcriptional responses, which promote chronic adaptation. In this review, we discuss the mechanisms by which mammals sense changes in O2 and CO2 and elicit adaptive responses to maintain homeostasis. We also discuss crosstalk between these pathways and how they may represent targets for therapeutic intervention in a range of pathological states.

Exercise-induced potentiation of the acute hypoxic ventilatory response: Neural mechanisms and implications for cerebral blood flow.

A given dose of hypoxia causes a greater increase in pulmonary ventilation during physical exercise than during rest, representing an exercise-induced potentiation of the acute hypoxic ventilatory response (HVR). This phenomenon occurs independently from hypoxic blood entering the contracting skeletal muscle circulation or metabolic byproducts leaving skeletal muscles, supporting the contention that neural mechanisms per se can mediate the HVR when humoral mechanisms are not at play. However, multiple neural mechanisms might be interacting intricately. First, we discuss the neural mechanisms involved in the ventilatory response to hypoxic exercise and their potential interactions. Current evidence does not support an interaction between the carotid chemoreflex and central command. In contrast, findings from some studies support synergistic interactions between the carotid chemoreflex and the muscle mechano- and metaboreflexes. Second, we propose hypotheses about potential mechanisms underlying neural interactions, including spatial and temporal summation of afferent signals into the medulla, short-term potentiation and sympathetically induced activation of the carotid chemoreceptors. Lastly, we ponder how exercise-induced potentiation of the HVR results in hyperventilation-induced hypocapnia, which influences cerebral blood flow regulation, with multifaceted potential consequences, including deleterious (increased central fatigue and impaired cognitive performance), inert (unchanged exercise) and beneficial effects (protection against excessive cerebral perfusion).

Association Between Dyscapnia, Ventilatory Variables, and Mortality in Patients With Acute Respiratory Distress Syndrome-A Retrospective Cohort Study.

Background: This study aimed to investigate the associations between dyscapnia, ventilatory variables, and mortality. We hypothesized that the association between mechanical power or ventilatory ratio and survival is mediated by dyscapnia. Methods: Patients with moderate or severe acute respiratory distress syndrome (ARDS), who received mechanical ventilation within the first 48 h after admission to the intensive care unit for at least 48 h, were included in this retrospective single-center study. Values of arterial carbon dioxide (PaCO2) were categorized into "hypercapnia" (PaCO2 ≥ 50 mm Hg), "normocapnia" (PaCO2 36-49 mmHg), and "hypocapnia" (PaCO2 ≤ 35 mm Hg). We used path analyses to assess the associations between ventilatory variables (mechanical power and ventilatory ratio) and mortality, where hypocapnia or hypercapnia were included as mediating variables. Results: Between December 2017 and April 2021, 435 patients were included. While there was a significant association between mechanical power and hypercapnia (BEM = 0.24 [95% CI: 0.15; 0.34], P < .01), there was no significant association between mechanical power or hypercapnia and ICU mortality. The association between mechanical power and intensive care unit (ICU) mortality was fully mediated by hypocapnia (BEM = -0.10 [95% CI: -0.19; 0.00], P = .05; BMO = 0.38 [95% CI: 0.13; 0.63], P < .01). Ventilatory ratio was significantly associated with hypercapnia (B = 0.23 [95% CI: 0.14; 0.32], P < .01). There was no significant association between ventilatory ratio, hypercapnia, and mortality. There was a significant effect of ventilatory ratio on mortality, which was fully mediated by hypocapnia (BEM = -0.14 [95% CI: -0.24; -0.05], P < .01; BMO = 0.37 [95% CI: 0.12; 0.62], P < .01). Conclusion: In mechanically ventilated patients with moderate or severe ARDS, the association between mechanical power and mortality was fully mediated by hypocapnia. Likewise, there was a mediating effect of hypocapnia on the association between ventilatory ratio and ICU mortality. Our results indicate that the debate on dyscapnia and outcome after ARDS should consider the impact of ventilatory variables.

The Effects of Hypocapnia and Hypercapnia on Intraoperative Bleeding, Surgical Field Quality, and Surgeon Satisfaction Level in Septorhinoplasty: A Prospective Randomized Clinical Study.

BACKGROUND: Septorhinoplasty (SRP) is one of the most commonly performed procedures in the world for functional and aesthetic purposes. The present study was aimed to compare the effects of hypocapnia and hypercapnia regarding the total amount of intraoperative bleeding, surgical field quality, and surgeon satisfaction level. METHODS: In this randomized prospective clinical study, eighty patients with American Society of Anesthesiologists I-II and were 18-45 years old scheduled for septorhinoplasty were randomly allocated to group hypocapnia [end-tidal carbon dioxide (EtCO2) 30 ± 2 mmHg] and group hypercapnia (EtCO2 40 ± 2 mmHg). We evaluated the total amount of intraoperative bleeding, the surgical field quality, surgeon satisfaction level, hemodynamics and peri- and postoperative adverse events. RESULTS: Group hypocapnia significantly reduced the total amount of intraoperative bleeding (p < 0.001). The surgical field quality and surgeon satisfaction level in group hypocapnia were significantly better than group hypercapnia (p < 0.001). EtCO2 levels of group hypocapnia were significantly lower than group hypercapnia at all time points (p < 0.001 for all time points). There were no significant differences between the groups in terms of heart rate and mean arterial pressure at all time points. There were no significant differences between the groups in terms of adverse events CONCLUSIONS: The results of this double-blind randomized clinical trial showed that reducing the amount of intraoperative bleeding for patients with hypocapnia undergoing SRP through known methods (e.g., reverse Trendelenburg head-up position, positive end-expiratory pressure limiting, controlled hypotension, and use of topical vasoconstrictors, corticosteroids, and tranexamic acid) would improve the quality of the surgical field and raise the surgeon satisfaction level. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Hypocapnia attenuates local skin thermal perception to innocuous warm and cool stimuli in normothermic resting humans.

When one is exposed to a stressful situation in their daily life, a common response is hyperventilation. Although the physiological significance of stress-induced hyperventilation remains uncertain, this response may blunt perception of the stress-inducing stimulus. This study examined the effects of voluntary hyperventilation and resultant hypocapnia on the local skin thermal detection threshold in normothermic resting humans. Local skin thermal detection thresholds were measured in 15 young adults (three females) under three breathing conditions: 1) spontaneous breathing (Control trial), 2) voluntary hypocapnic hyperventilation (HH trial), and 3) voluntary normocapnic hyperventilation (NH trial). Local skin thermal detection thresholds were measured using thermostimulators containing a Peltier element that were attached to the forearm and forehead. The temperature of the probe was initially equilibrated to the skin temperature, then gradually increased or decreased at a constant rate (±0.1 °C/s) until the participants felt warmth or coolness. The difference between the initial skin temperature and the local skin temperature at which the participant noticed warmth/coolness was assessed as an index of the local skin warm/cool detection threshold. Local detection of warm and cool stimuli did not differ between the Control and NH trials, but it was blunted in the HH trial as compared with the Control and NH trials, except for detection of warm stimuli on the forearm. These findings suggest that hyperventilation-induced hypocapnia, not hyperventilation per se, attenuates local skin thermal perception, though changes in responses to warm stimuli may not be clearly perceived at some skin areas (e.g., forearm).

Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023.

The respiratory system plays an integral part in maintaining acid-base homeostasis. Normal ventilation participates in the maintenance of an open buffer system, allowing for excretion of CO2 produced from the interaction of nonvolatile acids and bicarbonate. Quantitatively of much greater importance is the excretion of CO2 derived from volatile acids produced from the complete oxidation of fat and carbohydrate. A primary increase in CO2 tension of body fluids is the cause of respiratory acidosis and develops most commonly from one or more of the following: (1) disorders affecting gas exchange across the pulmonary capillary, (2) disorders of the chest wall and the respiratory muscles, and/or (3) inhibition of the medullary respiratory center. Respiratory alkalosis or primary hypocapnia is most commonly caused by disorders that increase alveolar ventilation and is defined by an arterial partial pressure of CO2 <35 mm Hg with subsequent alkalization of body fluids. Both disorders can lead to life-threatening complications, making it of paramount importance for the clinician to have a thorough understanding of the cause and treatment of these acid-base disturbances.

Microvascular effects of oxygen and carbon dioxide measured by vascular occlusion test in healthy volunteers.

BACKGROUND: Changes in near-infrared spectroscopy-derived regional tissue oxygen saturation (StO2) during a vascular occlusion test (VOT; ischemic provocation of microcirculation by rapid inflation and deflation of a tourniquet) allow estimating peripheral tissue O2 consumption (desaturation slope; DS), vascular reactivity (recovery slope; RS) and post-ischemic hyperperfusion (AUC-H). The effects of isolated alterations in the inspiratory fraction of O2 (FiO2) and changes in expiratory CO2 remain to be elucidated. Therefore, in this secondary analysis we determined the effects of standardized isolated instances of hypoxia, hyperoxia, hypocapnia and hypercapnia on the VOT-induced StO2 changes in healthy volunteers (n = 20) to establish reference values for future physiological studies. METHODS: StO2 was measured on the thenar muscle. Multiple VOTs were performed in a standardized manner: i.e. at room air (baseline), during hyperoxia (FiO2 1.0), mild hypoxia (FiO2 ≈ 0.11), and after a second baseline, during hypocapnia (end-tidal CO2 (etCO2) 2.5-3.0 vol%) and hypercapnia (etCO2 7.0-7.5 vol%) at room air. Differences in DS, RS, and AUC-H were tested using repeated-measures ANOVA. RESULTS: DS and RS remained constant during all applied conditions. AUC-H after hypoxia was smaller compared to hyperoxia (963 %*sec vs hyperoxia 1702 %*sec, P = 0.005), while there was no difference in AUC-H duration between hypoxia and baseline. The StO2 peak (after tourniquet deflation) during hypoxia was lower compared to baseline and hyperoxia (92 % vs 94 % and 98 %, P < 0.001). CONCLUSION: We conclude that in healthy volunteers at rest, common situations observed during anesthesia and intensive care such as exposure to hypoxia, hyperoxia, hypocapnia, or hypercapnia, did not affect peripheral tissue O2 consumption and vascular reactivity as assessed by VOT-induced changes in StO2. These observations may serve as reference values for future physiological studies. TRIAL REGISTRATION: This study represents a secondary analysis of an original study which has been registered at ClinicalTrials.gov nr: NCT02561052.

Carbon dioxide and MAPK signalling: towards therapy for inflammation.

Inflammation, although necessary to fight infections, becomes a threat when it exceeds the capability of the immune system to control it. In addition, inflammation is a cause and/or symptom of many different disorders, including metabolic, neurodegenerative, autoimmune and cardiovascular diseases. Comorbidities and advanced age are typical predictors of more severe cases of seasonal viral infection, with COVID-19 a clear example. The primary importance of mitogen-activated protein kinases (MAPKs) in the course of COVID-19 is evident in the mechanisms by which cells are infected with SARS-CoV-2; the cytokine storm that profoundly worsens a patient's condition; the pathogenesis of diseases, such as diabetes, obesity, and hypertension, that contribute to a worsened prognosis; and post-COVID-19 complications, such as brain fog and thrombosis. An increasing number of reports have revealed that MAPKs are regulated by carbon dioxide (CO2); hence, we reviewed the literature to identify associations between CO2 and MAPKs and possible therapeutic benefits resulting from the elevation of CO2 levels. CO2 regulates key processes leading to and resulting from inflammation, and the therapeutic effects of CO2 (or bicarbonate, HCO3-) have been documented in all of the abovementioned comorbidities and complications of COVID-19 in which MAPKs play roles. The overlapping MAPK and CO2 signalling pathways in the contexts of allergy, apoptosis and cell survival, pulmonary oedema (alveolar fluid resorption), and mechanical ventilation-induced responses in lungs and related to mitochondria are also discussed. Video Abstract.

Dose-dependent relationship between intra-procedural hypoxaemia or hypocapnia and postoperative delirium in older patients.

BACKGROUND: Previous studies indicated an association between impaired cerebral perfusion and post-procedural neurological disorders. We investigated whether intra-procedural hypoxaemia or hypocapnia are associated with delirium after surgery. METHODS: Inpatients ≥60 yr of age undergoing anaesthesia for surgical or interventional procedures between 2009 and 2020 at an academic healthcare network in the USA (Massachusetts) were included in this hospital registry study. The primary exposure was intra-procedural hypoxaemia, defined as peripheral oxygen saturation <90% for >2 cohering min. The co-primary exposure was hypocapnia during general anaesthesia, defined as end-tidal carbon dioxide pressure ≤25 mm Hg for >5 cohering min. The primary outcome was delirium within 7 days after surgery. RESULTS: Of 71 717 included patients, 1702 (2.4%) developed postoperative delirium, and hypoxaemia was detected in 2532 (3.5%). Of 42 894 patients undergoing general anaesthesia, 532 (1.2%) experienced hypocapnia. The occurrence of either hypoxaemia (adjusted odds ratio [ORadj]=1.71; 95% confidence interval [CI], 1.40-2.07; P<0.001) or hypocapnia (ORadj=1.77; 95% CI, 1.30-2.41; P<0.001) was associated with a higher risk of delirium within 7 days. Both associations were dependent on the magnitude, and increased with event duration (ORadj=1.03; 95% CI, 1.02-1.04; P<0.001 and ORadj=1.01; 95% CI, 1.00-1.01; P=0.005, for each minute increase in the longest continuous episode, respectively). There was no association between occurrence of hypercapnia and postoperative delirium (ORadj=1.24; 95% CI, 0.90-1.71; P=0.181). CONCLUSIONS: Intra-procedural hypoxaemia and hypocapnia were dose-dependently associated with a higher risk of postoperative delirium. These findings support maintaining normal gas exchange to avoid postoperative neurological disorders.

Effect of breathing re-training on end-tidal carbon-di-oxide in patients with asthma: a systematic review and meta-analysis.

OBJECTIVE: The review aims to determine the effect of breathing re-training on End-tidal carbon-di-oxide (ETCO2) in patients with asthma. DATA SOURCES: A systematic search of articles was performed in PubMed, Cochrane, PEDro, Scopus, and Ovid databases from their inception till May 2022. STUDY SELECTIONS: Studies were included if the patients were clinically diagnosed with mild-moderate asthma. Randomized controlled trials that monitored ETCO2 as a primary or secondary outcome were included. Studies were examined for potential risk of bias using the Revised Cochrane risk of bias tool by two independent reviewers. RESULTS: Eight articles were included. The trials used various techniques like Buteyko, Papworth, Biofeedback, and holistic approach. Quantitative analysis was conducted to examine the effects on ETCO2 at various time points. A significant large effect was seen on ETCO2 following breathing re-training post-treatment, 3 and 6 months post-intervention. CONCLUSION: There is moderate evidence for a significant effect of breathing re-training on ETCO2 in the short and long term in patients with asthma. However, high-quality randomized controlled trials using standardized measurement of ETCO2 are required to evaluate the effects of different breathing re-training techniques.

Effects of hyperventilation on oxygenation, apnea breaking points, diving response, and spleen contraction during serial static apneas.

PURPOSE: Hyperventilation is considered a major risk factor for hypoxic blackout during breath-hold diving, as it delays the apnea breaking point. However, little is known about how it affects oxygenation, the diving response, and spleen contraction during serial breath-holding. METHODS: 18 volunteers with little or no experience in freediving performed two series of 5 apneas with cold facial immersion to maximal duration at 2-min intervals. In one series, apnea was preceded by normal breathing and in the other by 15 s of hyperventilation. End-tidal oxygen and end-tidal carbon dioxide were measured before and after every apnea, and peripheral oxygen saturation, heart rate, breathing movements, and skin blood flow were measured continuously. Spleen dimensions were measured every 15 s. RESULTS: Apnea duration was longer after hyperventilation (133 vs 111 s). Hyperventilation reduced pre-apnea end-tidal CO2 (17.4 vs 29.0 mmHg) and post-apnea end-tidal CO2 (38.5 vs 40.3 mmHg), and delayed onset of involuntary breathing movements (112 vs 89 s). End-tidal O2 after apnea was lower in the hyperventilation trial (83.4 vs 89.4 mmHg) and so was the peripheral oxygen saturation nadir after apnea (90.6 vs 93.6%). During hyperventilation, the nadir peripheral oxygen saturation was lower in the last apnea than in the first (94.0% vs 86.7%). There were no differences in diving response or spleen volume reduction between conditions or across series. CONCLUSIONS: Serial apneas  revealed a previously undescribed aspect of hyperventilation; a progressively increased desaturation across the series, not observed after normal breathing and could heighten the risk of a blackout.

Hypocarbia is associated with adverse outcomes in hypoxic ischaemic encephalopathy (HIE).

AIM: Hypocarbia in the early postnatal period might exacerbate brain injury in babies with hypoxic ischaemic encephalopathy following birth asphyxia. This mini-review summarised studies on pCO2 values that were monitored periodically in term newborns with moderate/severe hypoxic-ischaemic encephalopathy and correlated with short or long-term outcomes. METHODS: We searched the databases MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), web of science and the Cochrane Library and identified nine studies. RESULTS: Among the nine included studies, therapeutic hypothermia was administered in seven studies. In most studies, blood pCO2 levels were measured from birth till 72 h of life or till the endpoint of therapeutic hypothermia. Eight studies showed that any hypocarbia (moderate or severe, or cumulative) was associated with an increased risk of adverse outcomes in the form of brain injury in MRI, death or neurodevelopmental disability. CONCLUSION: Hypocarbia could lead to adverse short-term and long-term outcomes despite therapeutic hypothermia in neonates with HIE. Hence, it is vital to monitor pCO2 levels closely in these infants and consider strategies to maintain pCO2 levels in the normal range.

Contribution of the carotid body to thermally mediated hyperventilation in humans.

Humans hyperventilate under heat and cold strain. This hyperventilatory response has detrimental consequences including acid-base dysregulation, dyspnoea, decreased cerebral blood flow and accelerated brain heating. The ventilatory response to hypoxia is exaggerated under whole-body heating and cooling, indicating that altered carotid body function might contribute to thermally mediated hyperventilation. To address whether the carotid body might contribute to heat- and cold-induced hyperventilation, we indirectly measured carotid body tonic activity via hyperoxia, and carotid body sensitivity via hypoxia, under graded heat and cold strain in 13 healthy participants in a repeated-measures design. We hypothesised that carotid body tonic activity and sensitivity would be elevated in a dose-dependent manner under graded heat and cold strain, thereby supporting its role in driving thermally mediated hyperventilation. Carotid body tonic activity was increased in a dose-dependent manner with heating, reaching 175% above baseline (P < 0.0005), and carotid body suppression with hyperoxia removed all of the heat-induced increase in ventilation (P = 0.9297). Core cooling increased carotid body activity by up to 250% (P < 0.0001), but maximal values were reached with mild cooling and thereafter plateaued. Carotid body sensitivity to hypoxia was profoundly increased by up to 180% with heat stress (P = 0.0097), whereas cooling had no detectable effect on hypoxic sensitivity. In summary, cold stress increased carotid body tonic activity and this effect was saturated with mild cooling, whereas heating had clear dose-dependent effects on carotid body tonic activity and sensitivity. These dose-dependent effects with heat strain indicate that the carotid body probably plays a primary role in driving heat-induced hyperventilation. KEY POINTS: Humans over-breathe (hyperventilate) when under heat and cold stress, and though this has detrimental physiological repercussions, the mechanisms underlying this response are unknown. The carotid body, a small organ that is responsible for driving hyperventilation in hypoxia, was assessed under incremental heat and cold strain. The carotid body drive to breathe, as indirectly assessed by transient hyperoxia, increased in a dose-dependent manner with heating, reaching 175% above baseline; cold stress similarly increased the carotid body drive to breathe, but did not show dose-dependency. Carotid body sensitivity, as indirectly assessed by hypoxic ventilatory responses, was profoundly increased by 70-180% with mild and severe heat strain, whereas cooling had no detectable effect. Carotid body hyperactivity and hypersensitivity are two interrelated mechanisms that probably underlie the increased drive to breathe with heat strain, whereas carotid body hyperactivity during mild cooling may play a subsidiary role in cold-induced hyperventilation.

Silent Hypoxia in COVID-19: A Case Series.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global crisis challenging the worldwide healthcare systems. Many patients present with a mismatch of profound hypoxemia and few signs of respiratory distress (i.e., silent hypoxemia). This particular clinical presentation is often cited, but data are limited. MAIN BODY: We describe dyspnea sensation as assessed by using the BORG scale in pulmonary patients admitted to the emergency room during a 4-week period and transferred to the respiratory department of Siloah Hospital, Hannover, Germany. From October 1 to November 1, 2020, 82 patients with hypoxemia defined as oxygen demand to achieve an oxygen saturation (SpO2) ≥92% were included. In 45/82 (55%) patients, SARS-CoV-2 was detected by PCR on admission. Among non-COVID patients, exacerbation of COPD was the main diagnosis (15/37, 41%). All subjects rated their perceived dyspnea using the modified Borg CR10 scale. Patients in the non-COVID group suffered from more dyspnea on the modified Borg CR10 scale (median 1, IQR: 0-2 vs. median 5, IQR: 3-6, p < 0.001). In multivariate analysis, "silent hypoxemia" as defined by the dyspnea Borg CR10 scale ≥5 was independently associated with COVID-19 and presence of severe hypocapnia with an odds ratio of 0.221 (95% confidence interval 0.054, 0.907, p 0.036). CONCLUSION: Among pulmonary patients with acute hypoxemia defined as oxygen demand, patients suffering from COVID-19 experience less dyspnea compared to non-COVID patients. "Silent" hypoxemia was more common in COVID-19 patients.

Two-handed facemask technique effectively causes hyperventilation in electroconvulsive therapy: an observational study.

BACKGROUND: Electroconvulsive therapy (ECT) remains the mainstay treatment option for patients with psychiatric diseases, such as severe depression. Although various anesthetic techniques provide adequate therapeutic seizures, hyperventilation is a useful adjunct to augment seizure duration and improve seizure quality. We investigated how to efficiently use a facemask to accomplish protocolized hyperventilation and evaluate its effect on ECT seizure. METHODS: We studied 60 patients aged ≥18 years who underwent ECT. The patients were divided into two groups according to the technique of facemask ventilation used: the one-handed (n = 30) and two-handed (n = 30) groups. Following anesthesia induction under preoxygenation conditions, hyperventilation induced hypocapnia in the one-handed facemask group with manual bag ventilation was compared to that in the two-handed facemask group with assisted pressure-controlled ventilation. Ictal and peri-ictal electroencephalogram parameters and cardiovascular responses were monitored and compared between the one-handed and two-handed groups. RESULTS: The two-handed technique demonstrated better electroencephalogram regularity and minimized cardiovascular stress compared to the one-handed technique. These conclusions come from the fact that the one-handed technique induced a substantial volume of leaks around the facemask (201.7 ± 98.6 mL/breath), whereas minimal leaks (25.8 ± 44.6 mL/breath) with stabler and higher ventilation rate led to greater inhaled minute ventilation in the two-handed group (the one-handed group, 9.52 ± 3.94 L/min; the two-handed group, 11.95 ± 2.29 L/min; p <  0.005). At the end of ECT treatment, all parameters of blood pressure and heart rate increased significantly in both groups equally, with lower SpO2 and more ST-segment depression on the electrocardiogram in the one-handed group. Comparing baseline values before anesthesia, ECT treatment significantly depressed ST-segment in both groups, while the degree of depression in ST-segment increased significantly in the one-handed group compared to that in the two-handed group. CONCLUSIONS: End-tidal carbon dioxide monitoring for hyperventilation can reliably ensure hypocapnia only in the two-handed group. In ECT, the two-handed technique assisted by pressure-controlled ventilation is an effective and practical method for hyperventilation to induce adequate therapeutic seizures. While, the two-handed group with sufficient preoxygenation did not cause more cardiovascular stress than the one-handed group. TRIAL REGISTRATION: UMIN Clinical Trials Registry 000046544, Date of registration 05/01/2022.

Validation of a new combined transcutaneous tcPCO2 and tcPO2 sensor in children in the operating theater.

BACKGROUND: Arterial blood gas analysis is the gold standard for monitoring of Pa CO2 and PaO2 during mechanical ventilation. However, continuous measurements would be preferred. Transcutaneous sensors continuously measure blood gases diffusing from the locally heated skin. These sensors have been validated in children mostly in intensive care settings. Accuracy in children during general anesthesia is largely unknown. AIMS: We conducted a study in children undergoing general anesthesia to validate the use and to determine the accuracy of continuous transcutaneous measurements of the partial pressures of PCO2 (tcPCO2 ) and PO2 (tcPO2 ). METHODS: A prospective observational study in a tertiary care pediatric hospital in The Netherlands, from April to October 2018, in children aged 0-18 years undergoing general anesthesia. Patients were included when endotracheally intubated and provided with an arterial catheter for regular blood sampling. Patients with a gestational age <31 weeks, burn victims, and patients with skin disease were excluded. TcPCO2 and tcPO2  measurements were performed with a SenTec OxiVenT™ sensor (SenTec AG). Accuracy was determined with an agreement analysis between arterial and transcutaneous PCO2 and PO2  values, and between arterial and endtidal PCO2 (etCO2 ) values, according to Bland and Altman, accounting for multiple measurements per subject. RESULTS: We included 53 patients (median age 4.1 years, IQR 0.7-14.4 years) and retrieved 175 samples. TcPCO2 -Pa CO2 agreement analysis provided a bias of 0.06 kPa (limits of agreement (LOA) -1.18 to 1.31), the etCO2 -Pa CO2 agreement showed a bias of -0.31 kPa (LOA -1.38 to 0.76). Results of the tcPO2 -PaO2 agreement showed a bias of 3.40 to 0.86* (mean tension) kPa. CONCLUSIONS: This study showed good agreement between Pa CO2 and tcPCO2 in children of all ages during general anesthesia. Both transcutaneous and endtidal CO2  measurements showed good accuracy. TcPO2 is only accurate under 6 months of age.

Impact of intraoperative hypocapnia on postoperative complications in laparoscopic surgery for colorectal cancer.

PURPOSE: In laparoscopic surgery (LS) for colorectal cancer (CRC), the relationship between intraoperative end-tidal carbon dioxide concentration (EtCO2) and surgery-related complications remains unexplored. This study assessed the impact of intraoperative EtCO2 on postoperative complications in LS for CRC. METHODS: In total, 909 patients who underwent LS for CRC were enrolled. Hypocapnia and hypercapnia were defined as EtCO2 < 35 mmHg and > 40 mmHg, respectively, and the relationships between hypocapnia or hypercapnia duration and postoperative complications were analyzed. RESULTS: The median (range) durations of hypocapnia and hypercapnia were 2.0 (0-8.3) h and 0.3 (0-5.8) h, respectively. Complications were observed in 208 cases (23.0%), which included 37 (4.1%) instances of anastomotic leakage and 86 (9.5%) of superficial surgical site infection (SSI). While the hypercapnia duration was not associated with the short-term outcomes, prolonged hypocapnia was significantly correlated with complications (p = 0.02), specifically superficial SSI (p = 0.005). Multivariate analyses adjusted for confounding factors confirmed that hypocapnia prolongation was an independent risk factor for postoperative superficial SSI [OR 1.19; 95% confidence interval (Cl) 1.03-1.36, p = 0.01]. CONCLUSION: Intraoperative hypocapnia may be a risk factor for postoperative complications, in particular superficial SSI, in LS for CRC.

Near-Infrared Spectroscopy Usefulness in Validation of Hyperventilation Test.

Background: The hyperventilation test is used in clinical practice for diagnosis and therapeutic purposes; however, in the absence of a standardized protocol, the procedure varies significantly, predisposing tested subjects to risks such as cerebral hypoxia and ischemia. Near-infrared spectroscopy (NIRS), a noninvasive technique performed for cerebral oximetry monitoring, was used in the present study to identify the minimum decrease in the end-tidal CO2 (ETCO2) during hyperventilation necessary to induce changes on NIRS. Materials and Methods: We recruited 46 volunteers with no preexisting medical conditions. Each subject was asked to breathe at a baseline rate (8−14 breaths/min) for 2 min and then to hyperventilate at a double respiratory rate for the next 4 min. The parameters recorded during the procedure were the regional cerebral oxyhemoglobin and deoxyhemoglobin concentrations via NIRS, ETCO2, and the respiratory rate. Results: During hyperventilation, ETCO2 values dropped (31.4 ± 12.2%) vs. baseline in all subjects. Changes in cerebral oximetry were observed only in those subjects (n = 30) who registered a decrease (%) in ETCO2 of 37.58 ± 10.34%, but not in the subjects (n = 16) for which the decrease in ETCO2 was 20.31 ± 5.6%. According to AUC-ROC analysis, a cutoff value of ETCO2 decrease >26% was found to predict changes in oximetry (AUC-ROC = 0.93, p < 0.0001). Seven subjects reported symptoms, such as dizziness, vertigo, and numbness, throughout the procedure. Conclusions: The rise in the respiratory rate alone cannot effectively predict the occurrence of a cerebral vasoconstrictor response induced by hyperventilation, and synchronous ETCO2 and cerebral oximetry monitoring could be used to validate this clinical test. NIRS seems to be a useful tool in predicting vasoconstriction following hyperventilation.

Dyspnea in Post-COVID Syndrome following Mild Acute COVID-19 Infections: Potential Causes and Consequences for a Therapeutic Approach.

Dyspnea, shortness of breath, and chest pain are frequent symptoms of post-COVID syndrome (PCS). These symptoms are unrelated to organ damage in most patients after mild acute COVID infection. Hyperventilation has been identified as a cause of exercise-induced dyspnea in PCS. Since there is a broad overlap in symptomatology with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), causes for dyspnea and potential consequences can be deduced by a stringent application of assumptions made for ME/CFS in our recent review papers. One of the first stimuli of respiration in exercise is caused by metabolic feedback via skeletal muscle afferents. Hyperventilation in PCS, which occurs early on during exercise, can arise from a combined disturbance of a poor skeletal muscle energetic situation and autonomic dysfunction (overshooting respiratory response), both found in ME/CFS. The exaggerated respiratory response aggravating dyspnea does not only limit the ability to exercise but further impairs the muscular energetic situation: one of the buffering mechanisms to respiratory alkalosis is a proton shift from intracellular to extracellular space via the sodium-proton-exchanger subtype 1 (NHE1), thereby loading cells with sodium. This adds to two other sodium loading mechanisms already operative, namely glycolytic metabolism (intracellular acidosis) and impaired Na+/K+ATPase activity. High intracellular sodium has unfavorable effects on mitochondrial calcium and metabolism via sodium-calcium-exchangers (NCX). Mitochondrial calcium overload by high intracellular sodium reversing the transport mode of NCX to import calcium is a key driver for fatigue and chronification. Prevention of hyperventilation has a therapeutic potential by keeping intracellular sodium below the threshold where calcium overload occurs.

Intraoperative end-tidal carbon dioxide and postoperative mortality in major abdominal surgery: a historical cohort study.

PURPOSE: There is a paucity of data on the effect of intraoperative end-tidal carbon dioxide (EtCO2) levels on postoperative mortality. The purpose of this study was to investigate the relationship between intraoperative EtCO2 and 90-day mortality in patients undergoing major abdominal surgery under general anesthesia. METHODS: We conducted a historical cohort study of patients undergoing major abdominal surgery under general anesthesia at Kyoto University Hospital. We measured the intraoperative EtCO2, and patients with a mean EtCO2 value < 35 mm Hg were classified as low EtCO2. The time effect was determined based on minutes below an EtCO2 of 35 mm Hg, and cumulative effects were evaluated by measuring the area under the threshold of 35 mm Hg for each patient. RESULTS: Of 4,710 patients, 1,374 (29%) had low EtCO2 and 55 (1.2%) died within 90 days of surgery. Multivariable Cox regression analysis-adjusted for age, American Society of Anesthesiologists Physical Status classification, sex, laparoscopic surgery, emergency surgery, blood loss, mean arterial pressure, duration of surgery, type of surgery, and chronic obstructive pulmonary disease-revealed an association between low EtCO2 and 90-day mortality (adjusted hazard ratio, 2.2; 95% confidence interval [CI], 1.2 to 3.8; P = 0.006). In addition, severity of low EtCO2 was associated with an increased 90-day mortality (area under the threshold; adjusted hazard ratio; 2.9, 95% CI, 1.2 to 7.4; P =0.02); for long-term exposure to an EtCO2 < 35 mm Hg (≥ 226 min), the adjusted hazard ratio for increased 90-day mortality was 2.3 (95% CI, 0.9 to 6.0; P = 0.08). CONCLUSION: A mean intraoperative EtCO2 < 35 mm Hg was associated with increased postoperative 90-day mortality.

RéSUMé: OBJECTIF: Il n'existe que très peu de données s'intéressant à l'effet du niveau peropératoire télé-expiratoire du dioxyde de carbone (EtCO2) sur la mortalité postopératoire. L'objectif de cette étude était d'examiner la relation entre l'EtCO2 peropératoire et la mortalité à 90 jours chez des patients subissant une chirurgie abdominale majeure sous anesthésie générale. MéTHODE: Nous avons réalisé une étude de cohorte historique portant sur des patients subissant une chirurgie abdominale majeure sous anesthésie générale à l'Hôpital universitaire de Kyoto. Nous avons mesuré l'EtCO2 peropératoire, et les patients avec une valeur moyenne d'EtCO2 < 35 mmHg ont été catégorisés comme EtCO2 faible. L'effet temps a été déterminé en fonction de la durée, en minutes, avec une EtCO2 inférieure à 35 mmHg, et les effets cumulatifs ont été évalués en mesurant l'aire sous le seuil de 35 mmHg pour chaque patient. RéSULTATS: Sur 4710 patients, 1374 (29 %) avaient une EtCO2 faible et 55 (1,2 %) sont décédés dans les 90 jours suivant la chirurgie. Une analyse de régression multivariée de Cox, ajustée pour tenir compte des facteurs suivants : âge, statut physique selon l'American Society of Anesthesiologists, sexe, chirurgie par laparoscopie, chirurgie d'urgence, pertes de sang, tension artérielle moyenne, durée de la chirurgie, type de chirurgie et maladie pulmonaire obstructive chronique, a révélé une association entre une EtCO2 faible et la mortalité à 90 jours (rapport de risque ajusté, 2,2; intervalle de confiance [IC] à 95 %, 1,2 à 3,8; P = 0,006). De plus, la sévérité de l'EtCO2 basse était associée à une augmentation de la mortalité à 90 jours (aire sous le seuil; rapport de risque ajusté; 2,9, IC 95 %, 1,2 à 7,4; P =0,02); pour une exposition à long terme à une EtCO2 < 35 mmHg (≥ 226 minutes), le rapport de risque ajusté pour une mortalité accrue à 90 jours était de 2,3 (IC 95 %, 0,9 à 6,0 ; P = 0,08). CONCLUSION: Une EtCO2 peropératoire moyenne < 35 mmHg était associée à une augmentation de la mortalité postopératoire à 90 jours.