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We sought to determine if the difference between PThis was a retrospective cohort study of adult patients who achieved return of spontaneous circulation (ROSC) after OHCA over 3 years. The primary exposure was the POf 698 OHCA patients transported to the hospitals, 381 had sustained ROSC and qualifying ENeither P

The lungs and kidneys are cooperative and interdependent organs that secure the homeostasis of the body. Volume and acid-base disorders sit at the nexus between these two systems. However, lung-kidney interactions affect the management of many other conditions, especially among critically ill patients. Therefore, management of one system cannot proceed without a thorough understanding of the physiology of the other. This installment of AJKD's Core Curriculum in Nephrology discusses the complex decision-making required in treating concomitant respiratory and kidney disorders. We cover systemic diseases of the pulmonary and glomerular capillaries, acute decompensated heart failure, management of acid-base disorders in acute respiratory distress syndrome and chronic obstructive pulmonary disease, and venous thromboembolism. Through a case-based approach, we weigh the factors affecting the risks and benefits of therapies to enable the reader to individualize treatment decisions in these challenging scenarios.

International audience; High-altitude exposure results in a hyperventilatory-induced respiratory alkalosis followed by renal compensation (bicarbonaturia) to return arterial blood pH (pHa) toward sea-level values. However, acid-base balance has not been comprehensively examined in both lowlanders and indigenous populations-where the latter are thought to be fully adapted to high altitude. The purpose of this investigation was to compare acid-base balance between acclimatizing lowlanders and Andean and Sherpa highlanders at various altitudes (∼3,800, ∼4,300, and ∼5,000 m). We compiled data collected across five independent high-altitude expeditions and report the following novel findings: 1) at 3,800 m, Andeans (n = 7) had elevated pHa compared with Sherpas (n = 12; P < 0.01), but not to lowlanders (n = 16; 9 days acclimatized; P = 0.09); 2) at 4,300 m, lowlanders (n = 16; 21 days acclimatized) had elevated pHa compared with Andeans (n = 32) and Sherpas (n = 11; both P < 0.01), and Andeans had elevated pHa compared with Sherpas (P = 0.01); and 3) at 5,000 m, lowlanders (n = 16; 14 days acclimatized) had higher pHa compared with both Andeans (n = 66) and Sherpas (n = 18; P < 0.01, and P = 0.03, respectively), and Andean and Sherpa highlanders had similar blood pHa (P = 0.65). These novel data characterize acid-base balance acclimatization and adaptation to various altitudes in lowlanders and indigenous highlanders.NEW & NOTEWORTHY Lowlander, Andean, and Sherpa arterial blood data were combined across five independent high-altitude expeditions in the United States, Nepal, and Peru to assess acid-base status at ∼3,800, ∼4,300, and ∼5,000 m. The main finding was that Andean and Sherpa highlander populations have more acidic arterial blood, due to elevated arterial carbon dioxide and similar arterial bicarbonate compared with acclimatizing lowlanders at altitudes ≥4,300 m.

Band 3 protein is a Cl-/HCO3- transporter on the red blood cell (RBC) surface with an important role in CO2 excretion. Greater band 3 expression by roughly 20% is found in people with the GP.Mur blood type. Intriguingly, a disproportional percentage of those with GP.Mur excel in field-and-track sports. Could higher band 3 activity benefit an individual's physical performance? This study explored the impact of GP.Mur/higher band 3 expression on ventilation and gas exchange during exhaustive exercise. We recruited 36 nonsmoking, elite male athletes (36.1% GP.Mur) from top sports universities to perform incremental exhaustive treadmill cardiopulmonary exercise testing (CPET). We analyzed CPET data with respect to absolute running time and to individual's % running time and % maximal O2 uptake. We found persistently higher respiratory frequencies and slightly lower tidal volume in GP.Mur athletes, resulting in a slightly larger increase of ventilation as the workload intensified. The expiratory duty cycle (Te/Ttot) was persistently longer and inspiratory duty cycle (Ti/Ttot) persistently shorter for GP.Mur subjects throughout the run. Consequently, PETCO2 (a surrogate marker for alveolar and arterial CO2 tension--PACO2 and PaCO2) was lower in the GP.Mur athletes during the early stages of exercise. In conclusion, athletes with GP.Mur and higher band 3 expression hyperventilate more during exercise in a pattern that utilizes a greater fraction of time for expiration than inspiration to increase the rate of CO2 excretion than increased tidal volume. This greater ventilation response reduced pCO2 and may help to extend exercise capacity in high-level sports.

Current American Thoracic Society (ATS) standards promote the use of race and ethnicity-specific reference equations for pulmonary function test (PFT) interpretation. There is rising concern that the use of race and ethnicity in PFT interpretation contributes to a false view of fixed differences between races and may mask the effects of differential exposures. This use of race and ethnicity may contribute to health disparities by norming differences in pulmonary function. In the United States and globally, race serves as a social construct that is based on appearance and reflects social values, structures, and practices. Classification of people into racial and ethnic groups differs geographically and temporally. These considerations challenge the notion that racial and ethnic categories have biological meaning and question the use of race in PFT interpretation. The ATS convened a diverse group of clinicians and investigators for a workshop in 2021 to evaluate the use of race and ethnicity in PFT interpretation. Review of evidence published since then that challenges current practice and continued discussion concluded with a recommendation to replace race and ethnicity-specific equations with race-neutral average reference equations, which must be accompanied with a broader re-evaluation of how PFTs are used to make clinical, employment, and insurance decisions. There was also a call to engage key stakeholders not represented in this workshop and a statement of caution regarding the uncertain effects and potential harms of this change. Other recommendations include continued research and education to understand the impact of the change, to improve the evidence for the use of PFTs in general, and to identify modifiable risk factors for reduced pulmonary function.

The contribution of veno-venous (VV) extracorporeal membrane oxygenation (ECMO) to systemic oxygen delivery is determined by the ratio of total extracorporeal blood flow (Q˙EC) to cardiac output (Q˙). Thermodilution-based measurements of Q˙ may be compromised by blood recirculating through the ECMO (recirculation fraction; Rf). We measured the effects of Q˙EC and Rf on classic thermodilution-based measurements of Q˙ in six anesthetized pigs. An ultrasound flow probe measured total aortic blood flow (Q˙A0) at the aortic root. Rf was quantified with the ultrasound dilution technique. Q˙EC was set to 0-125% of Q˙A0 and Q˙ was measured using a pulmonary artery catheter (PAC) in healthy and lung injured animals. PAC overestimated Q˙ (Q˙Pa) at all Q˙EC settings compared to Q˙A0. The mean bias between both methods was 2.1 L/min in healthy animals and 2.7 L/min after lung injury. The difference between Q˙Pa and Q˙A0 increased with an Q˙EC of 75-125%/Q˙A0 compared to QEC

One of the most dreaded complications of end stage liver disease is hepatorenal syndrome AKI (HRS-AKI; formally known as hepatorenal syndrome 1 [HRS-1]). HRS-AKI carries a high mortality, and treatment options are limited. Guidelines recommend terlipressin as the first-line treatment of HRS-AKI

Myocardial infarction (MI) is one of the leading causes of death worldwide. Prognosis and mortality rate are directly related to infarct size and post-infarction pathological heart remodeling, which can lead to heart failure. Hypoxic MI-affected areas increase the expression of hypoxia-inducible factor (HIF-1), inducing infarct size reduction and improving cardiac function. Hypoxia translocates HIF-1 to the nucleus, activating carbonic anhydrase IX (CAIX) transcription. CAIX regulates myocardial intracellular pH, critical for heart performance. Our objective was to investigate CAIX participation and relation with sodium bicarbonate transporters 1 (NBC1) and HIF-1 in cardiac remodeling after MI. We analyzed this pathway in an "in vivo" rat coronary artery ligation model and isolated cardiomyocytes maintained under hypoxia. Immunohistochemical studies revealed an increase in HIF-1 levels after 2 h of infarction. Similar results were observed in 2-h infarcted cardiac tissue (immunoblotting) and in hypoxic cardiomyocytes with a nuclear distribution (confocal microscopy). Immunohistochemical studies showed an increase CAIX in the infarcted area at 2 h, mainly distributed throughout the cell and localized in the plasma membrane at 24 h. Similar results were observed in 2 h in infarcted cardiac tissue (immunoblotting) and in hypoxic cardiomyocytes (confocal microscopy). NBC1 expression increased in cardiac tissue after 2 h of infarction (immunoblotting). CAIX and NBC1 interaction increases in cardiac tissue subjected to MI for 2h when CAIX is present (immunoprecipitation). These results suggest that CAIX interacts with NBC1 in our infarct model as a mechanism to prevent acidic damage in hypoxic tissue, making it a promising therapeutic target., Centro de Investigaciones Cardiovasculares, Comisión de Investigaciones Científicas de la provincia de Buenos Aires

To minimize transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus responsible for coronavirus disease (COVID-19), the U.S. Centers for Disease Control and Prevention and the World Health Organization recommend wearing face masks in public. Some have expressed concern that these may affect the cardiopulmonary system by increasing the work of breathing, altering pulmonary gas exchange and increasing dyspnea, especially during physical activity. These concerns have been derived largely from studies evaluating devices intentionally designed to severely affect respiratory mechanics and gas exchange. We review the literature on the effects of various face masks and respirators on the respiratory system during physical activity using data from several models: cloth face coverings and surgical masks, N95 respirators, industrial respirators, and applied highly resistive or high–dead space respiratory loads. Overall, the available data suggest that although dyspnea may be increased and alter perceived effort with activity, the effects on work of breathing, blood gases, and other physiological parameters imposed by face masks during physical activity are small, often too small to be detected, even during very heavy exercise. There is no current evidence to support sex-based or age-based differences in the physiological responses to exercise while wearing a face mask. Although the available data suggest that negative effects of using cloth or surgical face masks during physical activity in healthy individuals are negligible and unlikely to impact exercise tolerance significantly, for some individuals with severe cardiopulmonary disease, any added resistance and/or minor changes in blood gases may evoke considerably more dyspnea and, thus, affect exercise capacity.

The ongoing coronavirus disease (COVID-19) pandemic has been unprecedented on many levels, not least of which are the challenges in understanding the pathophysiology of these new critically ill patients. One widely reported phenomenon is that of a profoundly hypoxemic patient with minimal to no dyspnea out of proportion to the extent of radiographic abnormality and change in lung compliance. This apparently unique presentation, sometimes called "happy hypoxemia or hypoxia" but better described as "silent hypoxemia," has led to the speculation of underlying pathophysiological differences between COVID-19 lung injury and acute respiratory distress syndrome (ARDS) from other causes. We explore three proposed distinctive features of COVID-19 that likely bear on the genesis of silent hypoxemia, including differences in lung compliance, pulmonary vascular responses to hypoxia, and nervous system sensing and response to hypoxemia. In the context of known principles of respiratory physiology and neurobiology, we discuss whether these particular findings are due to direct viral effects or, equally plausible, are within the spectrum of typical ARDS pathophysiology and the wide range of hypoxic ventilatory and pulmonary vascular responses and dyspnea perception in healthy people. Comparisons between lung injury patterns in COVID-19 and other causes of ARDS are clouded by the extent and severity of this pandemic, which may underlie the description of "new" phenotypes, although our ability to confirm these phenotypes by more invasive and longitudinal studies is limited. However, given the uncertainty about anything unique in the pathophysiology of COVID-19 lung injury, there are no compelling pathophysiological reasons at present to support a therapeutic approach for these patients that is different from the proven standards of care in ARDS.

This randomized, placebo-controlled, double-blind study is the first to investigate whether acetazolamide, which reduces acute mountain sickness (AMS), inhibits short-term hypoxic pulmonary vasoconstriction, and also prevents high-altitude pulmonary edema (HAPE) in a fast-climbing ascent to 4,559 m. We found no statistically significant reduction in HAPE incidence or differences in hypoxic pulmonary artery pressures compared with placebo despite reductions in AMS and greater ventilation-induced arterial oxygenation. Our data do not support recommending acetazolamide for HAPE prevention.

Clinically evident high-altitude pulmonary edema (HAPE) is characterized by severe cyanosis, dyspnea, cough, and difficulty with physical exertion. This usually occurs within 1–2 days of ascent often with the additional stresses of any exercise and hypoventilation of sleep. The earliest events in evolving HAPE progress through clinically silent and then minimally recognized problems. The most important of these events involves an exaggerated elevation of pulmonary artery (PA) pressure in response to the ambient hypoxia. Hypoxic pulmonary vasoconstriction (HPV) is a rapid response with several phases. The first phase in both resistance arterioles and venules occurs within 5–10 min. This is followed by a second phase that further raises PA pressure by another 100% over the next 2–8 h. Combined with vasoconstriction and likely an unevenness in the regional strength of HPV, pressures in some microvascular regions with lesser arterial constriction rise to a level that initiates greater filtration of fluid into the interstitium. As pressures continue to rise local lymphatic clearance rates are exceeded and interstitial fluid begins to accumulate. Beyond elevation of transmural pressure gradients there is a dynamic noninjurious relaxation of microvascular and epithelial cell-cell contacts and an increase in transcellular vesicular transport which accelerate leakage. At some point with further pressure elevation, damage occurs with breaks of the barrier and bleeding into the alveolar space, a late-stage situation termed capillary stress failure. Earlier before there is fluid accumulation, alveolar hypoxia and hyperventilation-induced hypocapnia reduce the capacity of the alveolar epithelium to reabsorb sodium and water back into the interstitial space. More modest ascent which slows the rate of rise in PA pressure and allows for adaptive remodeling of the microvasculature, drugs which lower PA pressure, and those that can enhance fluid reabsorption will all forestall the deleterious early rise of microvascular pressures and diminished active alveolar fluid reabsorption that precede and underlie the development of HAPE.

Background: The stress of high altitude alters vascular permeability, which may be related to structural changes in the endothelial glycocalyx. We aimed to study these changes by measuring plasma c...

BackgroundAppropriate interpretation of pulmonary function tests (PFTs) involves the classification of observed values as within/outside the normal range based on a reference population of healthy individuals, integrating knowledge of physiological determinants of test results into functional classifications and integrating patterns with other clinical data to estimate prognosis. In 2005, the American Thoracic Society (ATS) and European Respiratory Society (ERS) jointly adopted technical standards for the interpretation of PFTs. We aimed to update the 2005 recommendations and incorporate evidence from recent literature to establish new standards for PFT interpretation.MethodsThis technical standards document was developed by an international joint Task Force, appointed by the ERS/ATS with multidisciplinary expertise in conducting and interpreting PFTs and developing international standards. A comprehensive literature review was conducted and published evidence was reviewed.ResultsRecommendations for the choice of reference equations and limits of normal of the healthy population to identify individuals with unusually low or high results are discussed. Interpretation strategies for bronchodilator responsiveness testing, limits of natural changes over time and severity are also updated. Interpretation of measurements made by spirometry, lung volumes and gas transfer are described as they relate to underlying pathophysiology with updated classification protocols of common impairments.ConclusionsInterpretation of PFTs must be complemented with clinical expertise and consideration of the inherent biological variability of the test and the uncertainty of the test result to ensure appropriate interpretation of an individual's lung function measurements.

Acute respiratory distress syndrome (ARDS) is a rapidly developing non-cardiogenic pulmonary edema caused by pulmonary and systemic infections or sterile tissue injuries that evoke a severe lung-damaging host inflammatory response. The lung loses its normal gas exchange efficiency with disruption of the tight permeability characteristics of the alveolar capillary barrier. Interstitial and subsequent alveolar edema lead to alveolar collapse/de-recruitment, reduced lung compliance and greater pulmonary vascular resistance, often with marked regional heterogeneity in severity. Regional heightened stress applied to surrounding normal or less injured lung from edematous and collapsed regions along with associated barotrauma, volutrauma and atelectrauma with mechanical or extreme spontaneous ventilatory efforts further propagate injury in a vicious cycle called ventilator induced lung injury. Resulting arterial hypoxemia and hypercapnia arise from the creation of regions of shunt and low ventilation-perfusion (VA/Q) ratios, in addition to creation of high VA/Q and dead space areas by blood flow obstruction with thrombosis and/or high ventilating pressures. The pathophysiology of ARDS is discussed in this article and focuses on changes in the lung parenchyma and vasculature that reduce compliance, increase vascular resistance and compromise maintenance of dry normally compliant alveolar space by active alveolar fluid clearance and passive lymphatic fluid clearance from the lung interstitium. The COVID-19 pandemic that has emerged with the novel coronavirus, SARS-CoV-2, has generated a new form of severe acute lung injury that resembles ARDS in many of its features, but has different characteristics in its earliest stages leading to more profound hypoxemia and loss of dyspnea perception with less radiologically evident lung injury, not described before in ARDS. Understanding the pathophysiological features of ARDS and COVID-19 lung injury is critical to the best use of supportive therapies such as low tidal volume ventilation, supplemental oxygen concentrations, positive end-expiratory pressure (PEEP), permissive hypercapnia, prone positioning and neuromuscular blockade.

During the ongoing coronavirus disease (COVID-19) pandemic, reports in social media and the lay press indicate that a subset of patients are presenting with severe hypoxemia in the absence of dyspnea, a problem unofficially referred to as "silent hypoxemia." To decrease the risk of complications in such patients, one proposed solution has been to have those diagnosed with COVID-19 but not sick enough to warrant admission monitor their arterial oxygenation by pulse oximetry at home and present for care when they show evidence of hypoxemia. Though the ease of use and low cost of pulse oximetry makes this an attractive option for identifying problems at an early stage, there are important considerations with pulse oximetry about which patients and providers may not be aware that can interfere with successful implementation of such monitoring programs. Only a few independent studies have examined the performance of pocket oximeters and smart phone-based systems, but the limited available data raise questions about their accuracy, particularly as saturation falls below 90%. There are also multiple sources of error in pulse oximetry that must be accounted for, including rapid fluctuations in measurements when the arterial oxygen pressure/tension falls on the steep portion of the dissociation curve, data acquisition problems when pulsatile blood flow is diminished, accuracy in the setting of severe hypoxemia, dyshemoglobinemias, and other problems. Recognition of these issues and careful counseling of patients about the proper means for measuring their oxygen saturation and when to seek assistance can help ensure successful implementation of needed monitoring programs.

Acidosis is common among critically ill patients, but current approaches to correct pH do not improve disease outcomes. During systemic acidosis, cells are either passively exposed to extracellular acidosis that other cells have generated (extrinsic acidosis) or they are exposed to acid that they generate and export into the extracellular space (intrinsic acidosis). Although endothelial repair following intrinsic acidosis has been studied, the impact of extrinsic acidosis on migration and angiogenesis is unclear. We hypothesized that extrinsic acidosis inhibits metabolism and migration but promotes capillary-like network formation in pulmonary microvascular endothelial cells (PMVECs). Extrinsic acidosis was modeled by titrating media pH. Two types of intrinsic acidosis were compared, including increasing cellular metabolism by chemically inhibiting carbonic anhydrases (CAs) IX and XII (SLC-0111) and with hypoxia. PMVECs maintained baseline intracellular pH for 24 h with both extrinsic and intrinsic acidosis. Whole cell CA IX protein expression was decreased by extrinsic acidosis but not affected by hypoxia. When extracellular pH was equally acidic, extrinsic acidosis suppressed glycolysis, whereas intrinsic acidosis did not. Extrinsic acidosis suppressed migration, but increased Matrigel network master junction and total segment length. CRISPR-Cas9 CA IX knockout PMVECs revealed an independent role of CA IX in promoting glycolysis, as loss of CA IX alone was accompanied by decreased hexokinase I and pyruvate dehydrogenase E1α expression and decreasing migration. 2-deoxy-d-glucose had no effect on migration but profoundly inhibited network formation and increased N-cadherin expression. Thus, we report that while extrinsic acidosis suppresses endothelial glycolysis and migration, it promotes network formation.

Hypoxia evokes a spectrum of acid–base changes from alkalosis to acidosis and alters many responses to hypoxia at non-genomic and genomic levels, in part via altered hypoxia-inducible factor (HIF) metabolism. Healthy people at altitude and persons hyperventilating to non-hypoxic stimuli can raise arterial pH as high as 7.7. In these circumstances, alkalosis reduces sympathetic tone, blunts hypoxic pulmonary vasoconstriction and cerebral vasodilation, and increases hemoglobin-oxygen affinity. With severe hypoxia owing to profoundly low arterial O2 content (hypoxemia) or poor perfusion (ischemia), metabolic and hypercapnic acidosis develops along with considerable lactate formation with pH falling to below 6.8. Although acidoses are considered deleterious to cell function and survival, they can be cytoprotective by various anti-inflammatory, anti-oxidant, and anti-apoptotic mechanisms. Attempts to correct acidosis under these circumstances concurrent with re-oxygenation efforts may be ill advised. This so-called ‘pH paradox’ or permissive acidosis may offer therapeutic possibilities. Rapidly growing cancers often outstrip their oxygen and nutrient delivery and metabolic waste disposal, thus limiting growth and metastatic potential. However, their excessive glycolysis and lactate formation may not necessarily represent oxygen insufficiency, but an attempt to provide sufficient amounts of small carbon intermediates to supply many synthetic pathways of cellular proliferation. In either case, there is expression and upregulation of many genes involved in acid–base homeostasis, in part by HIF-1α and HIF-2α signaling. Inhibition of these proteins or gene suppression may have important therapeutic application in cancer therapy.

Aims: To test the acute hemodynamic effect of acetazolamide in patients with pulmonary hypertension (PH) under ambient air and hypoxia.Methods: Patients with pulmonary arterial or chronic thromboembolic PH (PAH/CTEPH) undergoing right heart catheterization were included in this randomized, placebo-controlled, double-blinded, crossover trial. The main outcome, pulmonary vascular resistance (PVR), further hemodynamics, blood- and cerebral oxygenation were measured 1 h after intravenous administration of 500 mg acetazolamide or placebo-saline on ambient air (normoxia) and at the end of breathing hypoxic gas (FIO2 0.15, hypoxia) for 15 min.Results: 24 PH-patients, 71% men, mean ± SD age 59 ± 14 years, BMI 28 ± 5 kg/m2, PVR 4.7 ± 2.1 WU participated. Mean PVR after acetazolamide vs. placebo was 5.5 ± 3.0 vs. 5.3 ± 3.0 WU; mean difference (95% CI) 0.2 (−0.2–0.6, p = 0.341). Heart rate was higher after acetazolamide (79 ± 12 vs. 77 ± 11 bpm, p = 0.026), pH was lower (7.40 ± 0.02 vs. 7.42 ± 0.03, p = 0.002) but PaCO2 and PaO2 remained unchanged while cerebral tissue oxygenation increased (71 ± 6 vs. 69 ± 6%, p = 0.017). In acute hypoxia, acetazolamide decreased PVR by 0.4 WU (0.0–0.9, p = 0.046) while PaO2 and PaCO2 were not changed. No adverse effects occurred.Conclusions: In patients with PAH/CTEPH, i.v. acetazolamide did not change pulmonary hemodynamics compared to placebo after 1 hour in normoxia but it reduced PVR after subsequent acute exposure to hypoxia. Our findings in normoxia do not suggest a direct acute pulmonary vasodilator effect of acetazolamide. The reduction of PVR during hypoxia requires further corroboration. Whether acetazolamide improves PH when given over a prolonged period by stimulating ventilation, increasing oxygenation, and/or altering vascular inflammation and remodeling remains to be investigated.

The regulation and defense of intracellular pH is essential for homeostasis. Indeed, alterations in cerebrovascular acid-base balance directly affect cerebral blood flow (CBF) which has implications for human health and disease. For example, changes in CBF regulation during acid-base disturbances are evident in conditions such as chronic obstructive pulmonary disease and diabetic ketoacidosis. The classic experimental studies from the past 75+ years are utilized to describe the integrative relationships between CBF, carbon dioxide tension (PCO2 ), bicarbonate (HCO3 - ), and pH. These factors interact to influence 1) the time course of acid-base compensatory changes and the respective cerebrovascular responses (due to rapid exchange kinetics between arterial, extracellular fluid, and intracellular brain tissue). We propose that alterations in arterial [HCO3 - ] during acute respiratory acidosis/alkalosis contribute to cerebrovascular acid-base regulation; and 2) the regulation of CBF by direct changes in arterial versus extravascular/ interstitial PCO2 and pH - the latter recognized as the proximal compartment which alters vascular smooth muscle cell regulation of CBF. Taken together, these results substantiate two key ideas: first, that the regulation of CBF is affected by the severity of metabolic/respiratory disturbances, including the extent of partial/full acid-base compensation. Second, that the regulation of CBF is independent of arterial pH and that diffusion of CO2 across the blood-brain barrier is integral to altering perivascular extracellular pH. Overall, by realizing the integrative relationships between CBF, PCO2 , HCO3 - , and pH, experimental studies may provide insights to improve CBF regulation in clinical practice with treatment of systemic acid-base disorders. This article is protected by copyright. All rights reserved.

Patients who receive earlier treatment for acute exacerbations of chronic obstructive pulmonary disease (COPD) have a better prognosis, including earlier symptom resolution and reduced risk of future emergency-department visits (ED) or hospitalizations. However, many patients delay seeking care or do not report worsening symptoms to their healthcare provider. In this study, we aimed to understand how patients perceived their breathing symptoms and identify factors that led to seeking or delaying care for an acute exacerbation of COPD. We conducted semistructured interviews with 60 individuals following a recent COPD exacerbation. Participants were identified from a larger study of outpatients with COPD by purposive sampling by exacerbation type: 15 untreated, 15 treated with prednisone and/or antibiotics in the outpatient setting, 16 treated in an urgent care or ED setting, and 14 hospitalized. Data were analyzed using inductive content analysis. Participants were primarily male (97%) with a mean age of 69.1 ± 6.9 years, mean FEV

A feature of heart failure patients is exercise-induced hyperventilation, due to several causes including alteration of lung mechanics and gas diffusion, increased ventilation relative to CO2 production, elevated dead space ventilation, and overactive metaboreceptor and chemoreceptor reflexes.1 It is a well-established physiological concept that chemical ventilatory control depends and responds to afferent input, that is, arterial partial pressure of carbon dioxide (PaCO2) and of oxygen (PaO2), from the peripheral and central chemoreceptors to maintain PaCO2 and PaO2 within a specific and narrow range. However, this PaO2/PaCO2/pH-dependent regulation of ventilation seems too simplistic in several pathophysiological conditions including heart failure.

Carbonic anhydrase (CA) is present within many cells of the heart, lungs, and the vasculature. An understanding of its roles in cardiac muscle and vascular smooth muscle, the vascular endothelium and lungs, was not fully appreciated until the 1980s and even presently more functions are being discovered. Despite its presence and roles in the physiological functioning of the cardiovascular and respiratory systems, its inhibition in some clinical circumstances may be therapeutic. In this chapter, we will review the expression and functions of the enzyme in the heart, lungs, and vasculature as background to a comprehensive discussion of how the enzyme may be targeted and its function altered in various disease afflicting these organs. While activators of CA exist, to date no studies of these compounds have been undertaken beyond a few neurological conditions. Targeting CA has largely involved the use of inhibitors, particularly acetazolamide, the first clinically approved inhibitor and still most widely used in its class. Interestingly, acetazolamide once thought to only bind to CAs at relevant clinical concentrations has many actions independent of CA with relevance to the heart, lungs, and vasculature. These include aquaporin blockade, activation of several membrane ion channels, and oxygen radical scavenging to name a few. Inhibition of carbonic anhydrase and actions of acetazolamide unrelated to enzyme inhibition have possible benefits in heart failure, myocardial infarction, acute lung injury, and systemic and pulmonary hypertension.

We have previously demonstrated that inhibition of extracellularly oriented carbonic anhydrase (CA) isoforms protects the myocardium against ischemia‐reperfusion injury. In this study, our aim was to assess the possible further contribution of CA intracellular isoforms examining the actions of the highly diffusible cell membrane permeant inhibitor of CA, ethoxzolamide (ETZ). Isolated rat hearts, after 20 min of stabilization, were assigned to the following groups: (1) Nonischemic control: 90 min of perfusion; (2) Ischemic control: 30 min of global ischemia and 60 min of reperfusion (R); and (3) ETZ: ETZ at a concentration of 100 μM was administered for 10 min before the onset of ischemia and then during the first 10 min of reperfusion. In additional groups, ETZ was administered in the presence of SB202190 (SB, a p38MAPK inhibitor) or chelerythrine (Chel, a protein kinase C [PKC] inhibitor). Infarct size, myocardial function, and the expression of phosphorylated forms of p38MAPK, PKCε, HSP27, and Drp1, and calcineurin Aβ content were assessed. In isolated mitochondria, the Ca2+ response, Ca2+ retention capacity, and membrane potential were measured. ETZ decreased infarct size by 60%, improved postischemic recovery of myocardial contractile and diastolic relaxation increased P‐p38MAPK, P‐PKCε, P‐HSP27, and P‐Drp1 expression, decreased calcineurin content, and normalized calcium and membrane potential parameters measured in isolated mitochondria. These effects were significantly attenuated when ETZ was administered in the presence of SB or Chel. These data show that ETZ protects the myocardium and mitochondria against ischemia‐reperfusion injury through p38MAPK‐ and PKCε‐dependent pathways and reinforces the role of CA as a possible target in the management of acute cardiac ischemic diseases., Ethoxzolamide (ETZ) limits the infarct size and postischemic myocardial dysfunction. ETZ attenuates the postischemic damage of the mitochondrial state and dynamic. p38MAPK‐ and protein kinase C epsilon‐dependent pathways are involved in the cardioprotection by ETZ. ETZ appears as a new pharmacology agent against reperfusion injury.

This study examined the role and function of the kidney at high altitude in relation to fluid balance and the development of acute mountain sickness (AMS), avoiding confounders that have contributed to conflicting results in previous studies. We examined 18 healthy male resting volunteers (18-40 yr) not acclimatized to high altitude while on a controlled diet for 24 h at Lausanne (altitude: 560 m) followed by a period of 44 h after reaching the Regina Margherita hut (4,559 m) by helicopter. AMS scores peaked after 20 h at 4,559 m. AMS was defined as functional Lake Louise score ≥ 2. There were no significant differences between 10 subjects with and 8 subjects without AMS for urinary flow, fluid balance, and weight change. Sodium excretion rate was lower in those with AMS after 24 h at altitude. Microalbuminuria increased at altitude but was not different between the groups. Creatinine clearance was not affected by altitude or AMS, whereas clearances of sinistrin and p-aminohippuric acid decreased slightly, somewhat more in those without AMS. Plasma concentrations of epinephrine, norepinephrine, atrial natriuretic factor, and vasopressin increased whereas renin activity, angiotensin, and aldosterone decreased at altitude. Circulating hormone concentrations did not differ between those with and without AMS. Summarizing, in healthy resting young men flown by helicopter to 4,559 m, renal function was not affected by hypoxia except for minor microalbuminuria, high altitude diuresis did not occur, and AMS was not associated with salt and water retention or renal dysfunction.NEW & NOTEWORTHY Kidney function remained essentially unaffected and acute mountain sickness (AMS) was not associated with salt and water retention in healthy young men flown to and resting at the Margherita hut (4,559 m) under strictly controlled conditions maintaining water, salt, and food intake at pre-exposure levels. Thus, renal dysfunction and fluid retention are not essential factors contributing to the pathophysiology of AMS.

PURPOSE OF REVIEW: Respiratory acidosis is commonly present in patients with respiratory failure. The usual treatment of hypercapnia is to increase ventilation. During the recent surge of COVID-19, respiratory acidosis unresponsive to increased mechanical ventilatory support was common. Increasing mechanical ventilation comes at the expense of barotrauma and hemodynamic compromise from increasing positive end-expiratory pressures or minute ventilation. Treating acute respiratory acidemia with sodium bicarbonate remains controversial. RECENT FINDINGS: There are no randomized controlled trials of administration of sodium bicarbonate for respiratory acidemia. A recent review concluded that alkali therapy for mixed respiratory and metabolic acidosis might be useful but was based on the conflicting and not conclusive literature regarding metabolic acidosis. This strategy should not be extrapolated to treatment of respiratory acidemia. Low tidal volume ventilation in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) has beneficial effects associated with permissive hypercapnia. Whether the putative benefits will be negated by administration of alkali is not known. Hypercapnic acidosis is well tolerated, with few adverse effects as long as tissue perfusion and oxygenation are maintained. SUMMARY: There is a lack of clinical evidence that administration of sodium bicarbonate for respiratory acidosis has a net benefit; in fact, there are potential risks associated with it.

Pun, Matiram, Rachel Turner, Giacomo Strapazzon, Hermann Brugger, and Erik R. Swenson. Lower incidence of COVID-19 at high altitude: Facts and confounders. High Alt Med Biol. 21:217-222, 2020.-The rapid transmission, increased morbidity, and mortality of coronavirus disease 2019 (COVID-19) has exhausted many health care systems and the global economy. Large variations in COVID-19 prevalence and incidence have been reported across and within many countries worldwide; however, this remains poorly understood. The variability and susceptibility across the world have been mainly attributed to differing socioeconomic status, burden of chronic diseases, access to health care, strength of health care systems, and early or late adoption of control measures. Environmental factors such as pollution, ambient temperature, humidity, and seasonal weather patterns at different latitudes may influence how severe the pandemic is and the incidence of infection in any part of the world. In addition, recent epidemiological data have been used to propose that altitude of residence may not only influence those environmental features considered key to lesser viral transmission, but also susceptibility to more severe forms of COVID-19 through hypoxic-hypobaria driven genomic or nongenomic adaptations specific to high-altitude populations. In this review, we critically examine these factors and attempt to determine based upon available scientific and epidemiological data whether living in high-altitude regions might be protective against COVID-19 as recent publications have claimed.