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.

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.

Changes in lung mechanics and ventilation-perfusion match: comparison of pulmonary air- and thromboembolism in rats.

BACKGROUND: Pulmonary air embolism (AE) and thromboembolism lead to severe ventilation-perfusion defects. The spatial distribution of pulmonary perfusion dysfunctions differs substantially in the two pulmonary embolism pathologies, and the effects on respiratory mechanics, gas exchange, and ventilation-perfusion match have not been compared within a study. Therefore, we compared changes in indices reflecting airway and respiratory tissue mechanics, gas exchange, and capnography when pulmonary embolism was induced by venous injection of air as a model of gas embolism or by clamping the main pulmonary artery to mimic severe thromboembolism. METHODS: Anesthetized and mechanically ventilated rats (n = 9) were measured under baseline conditions after inducing pulmonary AE by injecting 0.1 mL air into the femoral vein and after occluding the left pulmonary artery (LPAO). Changes in mechanical parameters were assessed by forced oscillations to measure airway resistance, lung tissue damping, and elastance. The arterial partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2) were determined by blood gas analyses. Gas exchange indices were also assessed by measuring end-tidal CO2 concentration (ETCO2), shape factors, and dead space parameters by volumetric capnography. RESULTS: In the presence of a uniform decrease in ETCO2 in the two embolism models, marked elevations in the bronchial tone and compromised lung tissue mechanics were noted after LPAO, whereas AE did not affect lung mechanics. Conversely, only AE deteriorated PaO2, and PaCO2, while LPAO did not affect these outcomes. Neither AE nor LPAO caused changes in the anatomical or physiological dead space, while both embolism models resulted in elevated alveolar dead space indices incorporating intrapulmonary shunting. CONCLUSIONS: Our findings indicate that severe focal hypocapnia following LPAO triggers bronchoconstriction redirecting airflow to well-perfused lung areas, thereby maintaining normal oxygenation, and the CO2 elimination ability of the lungs. However, hypocapnia in diffuse pulmonary perfusion after AE may not reach the threshold level to induce lung mechanical changes; thus, the compensatory mechanisms to match ventilation to perfusion are activated less effectively.

Physiological Targets for Orthostatic Hypotension: Improving Nonpharmacological Interventions in Patients with Orthostatic Cerebral Hypoperfusion.

Orthostatic hypotension (OH) is a form of orthostatic intolerance (OI) and a key physiological indicator of autonomic dysfunction that is associated with an increased risk of major cerebrocardiovascular events. Symptoms of cerebral hypoperfusion have been reported in patients with OH, which worsens symptoms and increases the risk of syncope. Since pharmacological interventions increase blood pressure (BP) independent of posture and do not restore normal baroreflex control, nonpharmacological treatments are considered the foundation of OH management. While reductions in cerebral blood flow velocity (CBFv) during orthostatic stress are associated with a decrease in end-tidal CO2 (EtCO2) and hypocapnia in patients with OI, their contribution to the severity of OH is not well understood. These measures have been physiological targets in a wide variety of biofeedback interventions. This study explored the relationship between cardiovascular autonomic control, EtCO2 and cerebral hypoperfusion in patients (N = 72) referred for OI. Patients with systolic OH were more likely to be male, older, demonstrate reduced adrenal and vagal baroreflex sensitivity, and reduced cardiovagal control during head-up tilt (HUT) than patients without systolic OH. Greater reduction in CBFv during HUT was associated with a larger reduction in ETCO2 and systolic BP during HUT. While deficits in cardiovascular autonomic control played a more important role in systolic OH, reduced EtCO2 was a major contributor to orthostatic cerebral hypoperfusion. These findings suggest that biofeedback treatments targeting both the autonomic nervous system and EtCO2 should be part of nonpharmacological interventions complementing the standard of care in OH patients with symptoms of cerebral hypoperfusion.

Short-term mild hyperventilation on intracranial pressure, cerebral autoregulation, and oxygenation in acute brain injury patients: a prospective observational study.

Current guidelines suggest a target of partial pressure of carbon dioxide (PaCO2) of 32-35 mmHg (mild hypocapnia) as tier 2 for the management of intracranial hypertension. However, the effects of mild hyperventilation on cerebrovascular dynamics are not completely elucidated. The aim of this study is to evaluate the changes of intracranial pressure (ICP), cerebral autoregulation (measured through pressure reactivity index, PRx), and regional cerebral oxygenation (rSO2) parameters before and after induction of mild hyperventilation. Single center, observational study including patients with acute brain injury (ABI) admitted to the intensive care unit undergoing multimodal neuromonitoring and requiring titration of PaCO2 values to mild hypocapnia as tier 2 for the management of intracranial hypertension. Twenty-five patients were included in this study (40% female), median age 64.7 years (Interquartile Range, IQR = 45.9-73.2). Median Glasgow Coma Scale was 6 (IQR = 3-11). After mild hyperventilation, PaCO2 values decreased (from 42 (39-44) to 34 (32-34) mmHg, p < 0.0001), ICP and PRx significantly decreased (from 25.4 (24.1-26.4) to 17.5 (16-21.2) mmHg, p < 0.0001, and from 0.32 (0.1-0.52) to 0.12 (-0.03-0.23), p < 0.0001). rSO2 was statistically but not clinically significantly reduced (from 60% (56-64) to 59% (54-61), p < 0.0001), but the arterial component of rSO2 (ΔO2Hbi, changes in concentration of oxygenated hemoglobin of the total rSO2) decreased from 3.83 (3-6.2) µM.cm to 1.6 (0.5-3.1) µM.cm, p = 0.0001. Mild hyperventilation can reduce ICP and improve cerebral autoregulation, with minimal clinical effects on cerebral oxygenation. However, the arterial component of rSO2 was importantly reduced. Multimodal neuromonitoring is essential when titrating PaCO2 values for ICP management.

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 .

Cerebral uptake of microvesicles occurs in normocapnic but not hypocapnic passive hyperthermia in young healthy male adults.

Passive hyperthermia causes cerebral hypoperfusion primarily from heat-induced respiratory alkalosis. However, despite the cerebral hypoperfusion, it is possible that the mild alkalosis might help to attenuate cerebral inflammation. In this study, the cerebral exchange of extracellular vesicles (microvesicles), which are known to elicit pro-inflammatory responses when released in conditions of stress, were examined in hyperthermia with and without respiratory alkalosis. Ten healthy male adults were heated passively, using a warm water-perfused suit, up to core temperature + 2°C. Blood samples were taken from the radial artery and internal jugular bulb. Microvesicle concentrations were determined in platelet-poor plasma via cells expressing CD62E (activated endothelial cells), CD31+ /CD42b- (apoptotic endothelial cells), CD14 (monocytes) and CD45 (pan-leucocytes). Cerebral blood flow was measured via duplex ultrasound of the internal carotid and vertebral arteries to determine cerebral exchange kinetics. From baseline to poikilocapnic (alkalotic) hyperthermia, there was no change in microvesicle concentration from any cell origin measured (P-values all >0.05). However, when blood CO2 tension was normalized to baseline levels in hyperthermia, there was a marked increase in cerebral uptake of microvesicles expressing CD62E (P = 0.028), CD31+ /CD42b- (P = 0.003) and CD14 (P = 0.031) compared with baseline, corresponding to large increases in arterial but not jugular venous concentrations. In a subset of seven participants who underwent hypercapnia and hypocapnia in the absence of heating, there was no change in microvesicle concentrations or cerebral exchange, suggesting that hyperthermia potentiated the CO2 /pH-mediated cerebral uptake of microvesicles. These data provide insight into a potential beneficial role of respiratory alkalosis in heat stress. KEY POINTS: The hyperthermia-induced hyperventilatory response is observed in most humans, despite causing potentially harmful reductions in cerebral blood flow. We tested the hypothesis that the respiratory-induced alkalosis is associated with lower circulating microvesicle concentrations, specifically in the brain, despite the reductions in blood flow. At core temperature + 2°C with respiratory alkalosis, microvesicles derived from endothelial cells, monocytes and leucocytes were at concentrations similar to baseline in the arterial and cerebral venous circulation, with no changes in cross-brain microvesicle kinetics. However, when core temperature was increased by 2°C with CO2 /pH normalized to resting levels, there was a marked cerebral uptake of microvesicles derived from endothelial cells and monocytes. The CO2 /pH-mediated alteration in cerebral microvesicle uptake occurred only in hyperthermia. These new findings suggest that the heat-induced hyperventilatory response might serve a beneficial role by preventing potentially inflammatory microvesicle uptake in the brain.

AMPK facilitates the hypoxic ventilatory response through non-adrenergic mechanisms at the brainstem.

We recently demonstrated that the hypoxic ventilatory response (HVR) is facilitated by the AMP-activated protein kinase (AMPK) in catecholaminergic neural networks that likely lie downstream of the carotid bodies within the caudal brainstem. Here, we further subcategorise the neurons involved, by cross-comparison of mice in which the genes encoding the AMPK-α1 (Prkaa1) and AMPK-α2 (Prkaa2) catalytic subunits were deleted in catecholaminergic (TH-Cre) or adrenergic (PNMT-Cre) neurons. As expected, the HVR was markedly attenuated in mice with AMPK-α1/α2 deletion in catecholaminergic neurons, but surprisingly was modestly augmented in mice with AMPK-α1/α2 deletion in adrenergic neurons when compared against a variety of controls (TH-Cre, PNMT-Cre, AMPK-α1/α2 floxed). Moreover, AMPK-α1/α2 deletion in catecholaminergic neurons precipitated marked hypoventilation and apnoea during poikilocapnic hypoxia, relative to controls, while mice with AMPK-α1/α2 deletion in adrenergic neurons entered relative hyperventilation with reduced apnoea frequency and duration. We conclude, therefore, that AMPK-dependent modulation of non-adrenergic networks may facilitate increases in ventilatory drive that shape the classical HVR, whereas AMPK-dependent modulation of adrenergic networks may provide some form of negative feedback or inhibitory input to moderate HVR, which could, for example, protect against hyperventilation-induced hypocapnia and respiratory alkalosis.

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.

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.

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.

The physiological basis of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare dyspnoea-fatigue syndrome caused by a progressive increase in pulmonary vascular resistance and eventual right ventricular (RV) failure. In spite of extensive pulmonary vascular remodelling, lung function in PAH is generally well preserved, with hyperventilation and increased physiological dead space, but minimal changes in lung mechanics and only mild to moderate hypoxaemia and hypocapnia. Hypoxaemia is mainly caused by a low mixed venous oxygen tension from a decreased cardiac output. Hypocapnia is mainly caused by an increased chemosensitivity. Exercise limitation in PAH is cardiovascular rather than ventilatory or muscular. The extent of pulmonary vascular disease in PAH is defined by multipoint pulmonary vascular pressure-flow relationships with a correction for haematocrit. Pulsatile pulmonary vascular pressure-flow relationships in PAH allow for the assessment of RV hydraulic load. This analysis is possible either in the frequency domain or in the time domain. The RV in PAH adapts to increased afterload by an increased contractility to preserve its coupling to the pulmonary circulation. When this homeometric mechanism is exhausted, the RV dilates to preserve flow output by an additional heterometric mechanism. Right heart failure is then diagnosed by imaging of increased right heart dimensions and clinical systemic congestion signs and symptoms. The coupling of the RV to the pulmonary circulation is assessed by the ratio of end-systolic to arterial elastances, but these measurements are difficult. Simplified estimates of RV-pulmonary artery coupling can be obtained by magnetic resonance or echocardiographic imaging of ejection fraction.

Carbon dioxide levels in neonates: what are safe parameters?

There is no consensus on the optimal pCO2 levels in the newborn. We reviewed the effects of hypercapnia and hypocapnia and existing carbon dioxide thresholds in neonates. A systematic review was conducted in accordance with the PRISMA statement and MOOSE guidelines. Two hundred and ninety-nine studies were screened and 37 studies included. Covidence online software was employed to streamline relevant articles. Hypocapnia was associated with predominantly neurological side effects while hypercapnia was linked with neurological, respiratory and gastrointestinal outcomes and Retinpathy of prematurity (ROP). Permissive hypercapnia did not decrease periventricular leukomalacia (PVL), ROP, hydrocephalus or air leaks. As safe pCO2 ranges were not explicitly concluded in the studies chosen, it was indirectly extrapolated with reference to pCO2 levels that were found to increase the risk of neonatal disease. Although PaCO2 ranges were reported from 2.6 to 8.7 kPa (19.5-64.3 mmHg) in both term and preterm infants, there are little data on the safety of these ranges. For permissive hypercapnia, parameters described for bronchopulmonary dysplasia (BPD; PaCO2 6.0-7.3 kPa: 45.0-54.8 mmHg) and congenital diaphragmatic hernia (CDH; PaCO2 ≤ 8.7 kPa: ≤65.3 mmHg) were identified. Contradictory findings on the effectiveness of permissive hypercapnia highlight the need for further data on appropriate CO2 parameters and correlation with outcomes. IMPACT: There is no consensus on the optimal pCO2 levels in the newborn. There is no consensus on the effectiveness of permissive hypercapnia in neonates. A safe range of pCO2 of 5-7 kPa was inferred following systematic review.

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.

Impact of High-Frequency Oscillatory Ventilation Combined With Volume Guarantee on Lung Inflammatory Response in Infants With Acute Respiratory Distress Syndrome After Congenital Heart Surgery: A Randomized Controlled Trial.

OBJECTIVES: Congenital heart disease (CHD) after cardiopulmonary bypass can cause systemic inflammation, and its degree is closely related to the incidence of acute respiratory distress syndrome (ARDS). The purpose of this study was to determine the effectiveness of high-frequency oscillatory ventilation (HFOV) combined with volume guarantee (VG) in reducing systemic inflammation in infants with ARDS after cardiopulmonary bypass for congenital heart surgery. DESIGN: A randomized controlled trial. SETTING: Single-center study in a tertiary teaching hospital. PARTICIPANTS: A total of 58 infants with ARDS after congenital heart surgery were eligible and were randomized to the HFOV (n = 29) or the HFOV-VG (n = 29) between January 2020 and January 2021. INTERVENTIONS: Tracheal aspirate samples for the measurement of interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF-α) were obtained on days one, two, and three of HFOV or HFOV-VG ventilation. MEASUREMENTS AND MAIN RESULTS: The authors found a significantly increasing trend in the HFOV group mean values of IL-6, IL-8, and TNF-α (p < 0.05 on days two and three v day one), and IL-6, IL-8, and TNF-α levels were significantly higher on day three in the HFOV group versus the HFOV+VG group (p < 0.05). In addition, the incidences of hypocapnia and hypercapnia in infants supported with HFOV-VG were significantly lower (p < 0.05). Furthermore, the postoperative mechanical ventilation duration in the HFOV-VG group also was shorter than that in the HFOV group (p < 0.05). CONCLUSION: Compared with HFOV alone, HFOV-VG reduced proinflammatory systemic reactions after congenital cardiac surgery, decreased the incidences of hypercapnia and hypocapnia, and shortened the postoperative mechanical ventilation duration.

Optimal Targets of the First 24-h Partial Pressure of Carbon Dioxide in Patients with Cerebral Injury: Data from the MIMIC-III and IV Database.

BACKGROUND: It is generally believed that hypercapnia and hypocapnia will cause secondary injury to patients with craniocerebral diseases, but a small number of studies have shown that they may have potential benefits. We assessed the impact of partial pressure of arterial carbon dioxide (PaCO2) on in-hospital mortality of patients with craniocerebral diseases. The hypothesis of this research was that there is a nonlinear correlation between PaCO2 and in-hospital mortality in patients with craniocerebral diseases and that mortality rate is the lowest when PaCO2 is in a normal range. METHODS: We identified patients with craniocerebral diseases from Medical Information Mart for Intensive Care third and fourth edition databases. Cox regression analysis and restricted cubic splines were used to examine the association between PaCO2 and in-hospital mortality. RESULTS: Nine thousand six hundred and sixty patients were identified. A U-shaped association was found between the first 24-h PaCO2 and in-hospital mortality in all participants. The nadir for in-hospital mortality risk was estimated to be at 39.5 mm Hg (p for nonlinearity < 0.001). In the subsequent subgroup analysis, similar results were found in patients with traumatic brain injury, metabolic or toxic encephalopathy, subarachnoid hemorrhage, cerebral infarction, and other encephalopathies. Besides, the mortality risk reached a nadir at PaCO2 in the range of 35-45 mm Hg. The restricted cubic splines showed a U-shaped association between the first 24-h PaCO2 and in-hospital mortality in patients with other intracerebral hemorrhage and cerebral tumor. Nonetheless, nonlinearity tests were not statistically significant. In addition, Cox regression analysis showed that PaCO2 ranging 35-45 mm Hg had the lowest death risk in most patients. For patients with hypoxic-ischemic encephalopathy and intracranial infections, the first 24-h PaCO2 and in-hospital mortality did not seem to be correlated. CONCLUSIONS: Both hypercapnia and hypocapnia are harmful to most patients with craniocerebral diseases. Keeping the first 24-h PaCO2 in the normal range (35-45 mm Hg) is associated with lower death risk.

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.

Differential regional cerebrovascular reactivity to end-tidal gas combinations commonly seen during anaesthesia: A blood oxygenation level-dependent MRI observational study in awake adult subjects.

BACKGROUND: Regional cerebrovascular reactivity (rCVR) is highly variable in the human brain as measured by blood oxygenation level-dependent (BOLD) MRI to changes in both end-tidal CO 2 and O 2 . OBJECTIVES: We examined awake participants under carefully controlled end-tidal gas concentrations to assess how regional CVR changes may present with end-tidal gas changes seen commonly with anaesthesia. DESIGN: Observational study. SETTING: Tertiary care centre, Winnipeg, Canada. The imaging for the study occurred in 2019. SUBJECTS: Twelve healthy adult subjects. INTERVENTIONS: Cerebral BOLD response was studied under two end-tidal gas paradigms. First end-tidal oxygen (ETO 2 ) maintained stable whereas ETCO 2 increased incrementally from hypocapnia to hypercapnia (CO 2 ramp); second ETCO 2 maintained stable whereas ETO 2 increased from normoxia to hyperoxia (O 2 ramp). BOLD images were modeled with end-tidal gas sequences split into two equal segments to examine regional CVR. MAIN OUTCOME MEASURES: The voxel distribution comparing hypocapnia to mild hypercapnia and mild hyperoxia (mean F I O 2  = 0.3) to marked hyperoxia (mean F I O 2  = 0.7) were compared in a paired fashion ( P  < 0.005 to reach threshold for voxel display). Additionally, type analysis was conducted on CO 2 ramp data. This stratifies the BOLD response to the CO 2 ramp into four categories of CVR slope based on segmentation (type A; +/+slope: normal response, type B +/-, type C -/-: intracranial steal, type D -/+.) Types B to D represent altered responses to the CO 2 stimulus. RESULTS: Differential regional responsiveness was seen for both end-tidal gases. Hypocapnic regional CVR was more marked than hypercapnic CVR in 0.3% of voxels examined ( P  < 0.005, paired comparison); the converse occurred in 2.3% of voxels. For O 2 , mild hyperoxia had more marked CVR in 0.2% of voxels compared with greater hyperoxia; the converse occurred in 0.5% of voxels. All subjects had altered regional CO 2 response based on Type Analysis ranging from 4 ±â€Š2 to 7 ±â€Š3% of voxels. CONCLUSION: In awake subjects, regional differences and abnormalities in CVR were observed with changes in end-tidal gases common during the conduct of anaesthesia. On the basis of these findings, consideration could be given to minimising regional CVR fluctuations in patients-at-risk of neurological complications by tighter control of end-tidal gases near the individual's resting values.