Genetic polymorphisms and expression of Rhesus blood group RHCE are associated with 2,3-bisphosphoglycerate in humans at high altitude.

Red blood cell (RBC) metabolic reprogramming upon exposure to high altitude contributes to physiological human adaptations to hypoxia, a multifaceted process critical to health and disease. To delve into the molecular underpinnings of this phenomenon, first, we performed a multi-omics analysis of RBCs from six lowlanders after exposure to high-altitude hypoxia, with longitudinal sampling at baseline, upon ascent to 5,100 m and descent to sea level. Results highlighted an association between erythrocyte levels of 2,3-bisphosphoglycerate (BPG), an allosteric regulator of hemoglobin that favors oxygen off-loading in the face of hypoxia, and expression levels of the Rhesus blood group RHCE protein. We then expanded on these findings by measuring BPG in RBCs from 13,091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. These data informed a genome-wide association study using BPG levels as a quantitative trait, which identified genetic polymorphisms in the region coding for the Rhesus blood group RHCE as critical determinants of BPG levels in erythrocytes from healthy human volunteers. Mechanistically, we suggest that the Rh group complex, which participates in the exchange of ammonium with the extracellular compartment, may contribute to intracellular alkalinization, thus favoring BPG mutase activity.

Are coagulation profiles in Andean highlanders with excessive erythrocytosis favouring hypercoagulability?

Chronic mountain sickness is a maladaptive syndrome that affects individuals living permanently at high altitude and is characterized primarily by excessive erythrocytosis (EE). Recent results concerning the impact of EE in Andean highlanders on clotting and the possible promotion of hypercoagulability, which can lead to thrombosis, were contradictory. We assessed the coagulation profiles of Andeans highlanders with and without excessive erythrocytosis (EE+ and EE-). Blood samples were collected from 30 EE+ and 15 EE- in La Rinconada (Peru, 5100-5300 m a.s.l.), with special attention given to the sampling pre-analytical variables. Rotational thromboelastometry tests were performed at both native and normalized (40%) haematocrit using autologous platelet-poor plasma. Thrombin generation, dosages of clotting factors and inhibitors were measured in plasma samples. Data were compared between groups and with measurements performed at native haematocrit in 10 lowlanders (LL) at sea level. At native haematocrit, in all rotational thromboelastometry assays, EE+ exhibited hypocoagulable profiles (prolonged clotting time and weaker clot strength) compared with EE- and LL (all P < 0.01). At normalized haematocrit, clotting times were normalized in most individuals. Conversely, maximal clot firmness was normalized only in FIBTEM and not in EXTEM/INTEM assays, suggesting abnormal platelet activity. Thrombin generation, levels of plasma clotting factors and inhibitors, and standard coagulation assays were mostly normal in all groups. No highlanders reported a history of venous thromboembolism based on the dedicated survey. Collectively, these results indicate that EE+ do not present a hypercoagulable profile potentially favouring thrombosis.

Making a virtue out of an evil: Are red blood cells from chronic mountain sickness patients eligible for transfusions?

We investigated highlanders, permanently living at an altitude of 5100 m and compared Chronic Mountain Sickness (CMS) patients with control volunteers. While we found differences in systemic parameters such as blood oxygen content, hematocrit, hemoglobin concentration, and blood viscosity, the mechanical and rheological properties of single red blood cells did not differ between the two investigated groups.

Expedition 5300: limits of human adaptations in the highest city in the world.

Exposure to chronic hypobaric hypoxia imposes a significant physiological burden to more than 80 million humans living above 2500 m throughout the world. Among them, 50 000 live in the world's highest city, La Rinconada, located at 5000-5300 m in southern Peru. Expedition 5300 is the first scientific and medical programme led in La Rinconada to investigate the physiological adaptations and altitude-related health issues in this unique population. Dwellers from La Rinconada have very high haemoglobin concentration (20.3 ± 2.4 g/dL; n = 57) and those with chronic mountain sickness (CMS) exhibit even higher concentrations (23.1 ± 1.7 g/dL; n = 150). These values are associated with large total haemoglobin mass and blood volume, without an associated iron deficit. These changes in intravascular volumes lead to a substantial increase in blood viscosity, which is even larger in CMS patients. Despite these large haematological changes, 24 h blood pressure monitoring is essentially normal in La Rinconada, but some results suggest impaired vascular reactivity. Echocardiography revealed large right heart dilatation and high pulmonary arterial pressure as well as left ventricle concentric remodelling and grade I diastolic dysfunction. These changes in heart dimension and function tend to be more severe in highlanders with CMS. Polygraphy evaluations revealed a large reduction in nocturnal pulse oxygen saturation (median SpO2  = 79%), which is even more severe in CMS patients who also tended to show a higher oxygen desaturation index. The population of La Rinconada offers a unique opportunity to investigate the human responses to chronic severe hypoxia, at an altitude that is probably close to the maximum altitude human beings can permanently tolerate without presenting major health issues.

A three-step support strategy for relatives of patients dying in the intensive care unit: a cluster randomised trial.

BACKGROUND: In relatives of patients dying in intensive care units (ICUs), inadequate team support can increase the prevalence of prolonged grief and other psychological harm. We aimed to evaluate whether a proactive communication and support intervention would improve relatives' outcomes. METHODS: We undertook a prospective, multicentre, cluster randomised controlled trial in 34 ICUs in France, to compare standard care with a physician-driven, nurse-aided, three-step support strategy for families throughout the dying process, following a decision to withdraw or withhold life support. Inclusion criteria were relatives of patients older than 18 years with an ICU length of stay 2 days or longer. Participating ICUs were randomly assigned (1:1 ratio) into an intervention cluster and a control cluster. The randomisation scheme was generated centrally by a statistician not otherwise involved in the study, using permutation blocks of non-released size. In the intervention group, three meetings were held with relatives: a family conference to prepare the relatives for the imminent death, an ICU-room visit to provide active support, and a meeting after the patient's death to offer condolences and closure. ICUs randomly assigned to the control group applied their best standard of care in terms of support and communication with relatives of dying patients. The primary endpoint was the proportion of relatives with prolonged grief (measured with PG-13, score ≥30) 6 months after the death. Analysis was by intention to treat, with the bereaved relatives as the unit of observation. The study is registered with ClinicalTrials.gov, NCT02955992. FINDINGS: Between Feb 23, 2017, and Oct 8, 2019, we enrolled 484 relatives of ICU patients to the intervention group and 391 to the control group. 379 (78%) relatives in the intervention group and 309 (79%) in the control group completed the 6-month interview to measure the primary endpoint. The intervention significantly reduced the number of relatives with prolonged grief symptoms (66 [21%] vs 57 [15%]; p=0·035) and the median PG-13 score was significantly lower in the intervention group than in the control group (19 [IQR 14-26] vs 21 [15-29], mean difference 2·5, 95% CI 1·04-3·95). INTERPRETATION: Among relatives of patients dying in the ICU, a physician-driven, nurse-aided, three-step support strategy significantly reduced prolonged grief symptoms. FUNDING: French Ministry of Health.

Critically ill patients with severe infections related to Geotrichum species: A French retrospective multicentre study.

OBJECTIVES: Geotrichum spp can be responsible for severe infections in immunocompromised patients. We aim to describe Geotrichum-related infections in the ICU and to assess risk factors of mortality. METHODS: Retrospective multicentre study, conducted in 14 French ICUs between 2002 and 2018, including critically ill adult patients with proven or probable infection related to Geotrichum species. Data were obtained from the medical charts. RESULTS: Thirty-six patients, median age 60 years IQR [53; 66] were included. Most of the patients had haematological malignancies (78%). The reason for ICU admission was shock in half of the patients (n = 19, 53%) and respiratory failure in thirteen patients (36%). Median SOFA score was 8.5 IQR [7; 15]. Time between ICU admission and fungal diagnosis was 2.5 days [-1; 4]. Infection was disseminated in 27 (75%) patients with positive blood cultures in 25 patients (69%). Thirty patients (83%) received curative antifungal treatment in the ICU, in a median time of 1 day [0;1] after ICU admission. Twenty-four patients (67%) died in the ICU and hospital mortality rate was 69%. The number and extent of organ failures, as represented by SOFA score, were associated with mortality. CONCLUSIONS: This study demonstrates poor outcome in critically ill patients with Geotrichum-related infections, which encourages a high level of suspicion.

Changes in cardiac function following a speed ascent to the top of Europe at 4808 m.

PURPOSE: Both prolonged exercise and acute high-altitude exposure are known to induce cardiac changes. We sought to describe the cardiac responses to speed climbing at high-altitude, including left ventricular (LV) performance assessment using the myocardial work index (MWI), a new index derived from 2D speckle tracking echocardiography (STE). METHODS: Eleven elite alpinists (9 males, age: 26 ± 4 years) were evaluated before and immediately after a speed ascent of the Mont-Blanc (4808 m) by echocardiography using conventional measurements as well as STE and MWI computation with derivate parameters as global work efficiency (GWE) or global wasted work (GWW). RESULTS: Athletes performed a long-duration (8 h 58 min ± 60 min) and intense (78 ± 4% of maximal heart rate) ascent under gradual hypoxic conditions (minimal SpO2 at 4808 m: 71 ± 4%). Hypoxic exercise-induced cardiac fatigue was observed post-ascent with a change in right ventricular (RV) and LV systolic function (RV fractional area change: - 20 ± 23%, p = 0.01; LV global longitudinal strain change: - 8 ± 9%, p = 0.02), as well as LV geometry and RV-LV interaction alterations with emergence of a D-shape septum in 5/11 (46%) participants associated with RV pressure overload (mean pulmonary arterial pressure change: + 55 ± 20%, p < 0.001). Both MWI and GWE were reduced post-ascent (- 21 ± 16%, p = 0.004 and - 4 ± 4%, p = 0.007, respectively). Relative decrease in MWI and GWE were inversely correlated with increase in GWW (r = - 0.86, p = 0.003 and r = -0.97, p < 0.001, respectively). CONCLUSIONS: Prolonged high-altitude speed climbing in elite climbers is associated with RV and LV function changes with a major interaction alteration. MWI, assessing the myocardial performance, could be a new tool for evaluating LV exercise-induced cardiac fatigue.

Effect of a speed ascent to the top of Europe on cognitive function in elite climbers.

PURPOSE: The combined effects of acute hypoxia and exercise on cognition remain to be clarified. We investigated the effect of speed climbing to high altitude on reactivity and inhibitory control in elite climbers. METHODS: Eleven elite climbers performed a speed ascent of the Mont-Blanc (4810 m) and were evaluated pre- (at 1000 m) and immediately post-ascent (at 3835 m). In both conditions, a Simon task was done at rest (single-task session, ST) and during a low-intensity exercise (dual-task session, DT). Prefrontal cortex (PFC) oxygenation and middle cerebral artery velocity (MCAv) were monitored using near-infrared spectroscopy and transcranial Doppler, respectively, during the cognitive task. Self-perceived mental fatigue and difficulty to perform the cognitive tests were estimated using a visual analog scale. Heart rate and pulse oxygenation (SpO2) were monitored during the speed ascent. RESULTS: Elite climbers performed an intense (~ 50% of the time ≥ 80% of maximal heart rate) and prolonged (8h58 ± 6 min) exercise in hypoxia (minimal SpO2 at 4810 m: 78 ± 4%). Reaction time and accuracy during the Simon task were similar pre- and post-ascent (374 ± 28 ms vs. 385 ± 39 ms and 6 ± 4% vs. 5 ± 4%, respectively; p > 0.05), despite a reported higher mental fatigue and difficulty to perform the Simon task post-ascent (all p < 0.05). The magnitude of the Simon effect was unaltered (p > 0.05), suggesting a preserved cognitive control post-ascent. Pattern of PFC oxygenation and MCAv differed between pre- and post-ascent as well as between ST and DT conditions. CONCLUSIONS: Cognitive control is not altered in elite climbers after a speed ascent to high-altitude despite substantial cerebral deoxygenation and fatigue perception.

Early hyperoxemia is associated with lower adjusted mortality after severe trauma: results from a French registry.

BACKGROUND: Hyperoxemia has been associated with increased mortality in critically ill patients, but little is known about its effect in trauma patients. The objective of this study was to assess the association between early hyperoxemia and in-hospital mortality after severe trauma. We hypothesized that a PaO2 ≥ 150 mmHg on admission was associated with increased in-hospital mortality. METHODS: Using data issued from a multicenter prospective trauma registry in France, we included trauma patients managed by the emergency medical services between May 2016 and March 2019 and admitted to a level I trauma center. Early hyperoxemia was defined as an arterial oxygen tension (PaO2) above 150 mmHg measured on hospital admission. In-hospital mortality was compared between normoxemic (150 > PaO2 ≥ 60 mmHg) and hyperoxemic patients using a propensity-score model with predetermined variables (gender, age, prehospital heart rate and systolic blood pressure, temperature, hemoglobin and arterial lactate, use of mechanical ventilation, presence of traumatic brain injury (TBI), initial Glasgow Coma Scale score, Injury Severity Score (ISS), American Society of Anesthesiologists physical health class > I, and presence of hemorrhagic shock). RESULTS: A total of 5912 patients were analyzed. The median age was 39 [26-55] years and 78% were male. More than half (53%) of the patients had an ISS above 15, and 32% had traumatic brain injury. On univariate analysis, the in-hospital mortality was higher in hyperoxemic patients compared to normoxemic patients (12% versus 9%, p < 0.0001). However, after propensity score matching, we found a significantly lower in-hospital mortality in hyperoxemic patients compared to normoxemic patients (OR 0.59 [0.50-0.70], p < 0.0001). CONCLUSION: In this large observational study, early hyperoxemia in trauma patients was associated with reduced adjusted in-hospital mortality. This result contrasts the unadjusted in-hospital mortality as well as numerous other findings reported in acutely and critically ill patients. The study calls for a randomized clinical trial to further investigate this association.

Compared Efficacy of Four Preoxygenation Methods for Intubation in the ICU: Retrospective Analysis of McGrath Mac Videolaryngoscope Versus Macintosh Laryngoscope (MACMAN) Trial Data.

OBJECTIVES: Severe hypoxemia is the most common serious adverse event during endotracheal intubation. Preoxygenation is performed routinely as a preventive measure. The relative efficacy of the various available preoxygenation devices is unclear. Here, our objective was to assess associations between preoxygenation devices and pulse oximetry values during endotracheal intubation. DESIGN: Post hoc analysis of data from a multicenter randomized controlled superiority trial (McGrath Mac Videolaryngoscope Versus Macintosh Laryngoscope [MACMAN]) comparing videolaryngoscopy to Macintosh laryngoscopy for endotracheal intubation in critical care. SETTING: Seven French ICUs. PATIENTS: Three-hundred nineteen of the 371 critically ill adults requiring endotracheal intubation who were included in the MACMAN trial. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Minimal pulse oximetry value during endotracheal intubation was the primary endpoint. We also sought risk factors for pulse oximetry below 90%. Of 319 patients, 157 (49%) had bag-valve-mask, 71 (22%) noninvasive ventilation, 71 (22%) non-rebreathing mask, and 20 (7%) high-flow nasal oxygen for preoxygenation. Factors independently associated with minimal pulse oximetry value were the Simplified Acute Physiology Score II severity score (p = 0.03), baseline pulse oximetry (p < 0.001), baseline PaO2/FIO2 ratio (p = 0.02), and number of laryngoscopies (p = 0.001). The only independent predictors of pulse oximetry less than 90% were baseline pulse oximetry (odds ratio, 0.71; 95% CI, 0.64-0.79; p < 0.001) and preoxygenation device: with bag-valve-mask as the reference, odds ratios were 1.10 (95% CI, 0.25-4.92) with non-rebreathing mask, 0.10 (95% CI, 0.01-0.80) with noninvasive ventilation, and 5.75 (95% CI, 1.15-28.75) with high-flow nasal oxygen. CONCLUSIONS: Our data suggest that the main determinants of hypoxemia during endotracheal intubation may be related to critical illness severity and to preexisting hypoxemia. The differences across preoxygenation methods suggest that noninvasive ventilation may deserve preference in patients with marked hypoxemia before endotracheal intubation. Ongoing studies will provide further clarification about the optimal preoxygenation method for endotracheal intubation in critically ill patients.

Intraoperative management of brain-dead organ donors by anesthesiologists during an organ procurement procedure: results from a French survey.

BACKGROUND: This study aimed at describing usual anesthetic practices for brain-dead donors (BDD) during an organ procurement (OP) procedure and to assess the knowledge and self-confidence of French anesthesiologists with this practice. METHODS: An electronic and anonymous survey with closed-questions about anesthetic management of BDD was distributed to French anesthesiologists via the mailing list of the French Society of Anesthesiology and Intensive Care Medicine. RESULTS: Four hundred fifty-eight responses were analyzed. Respondents were mainly attending physicians with more than 10 years of clinical experience. 78% of them declared being cognizant of guidelines regarding management of BDD. Advanced hemodynamic monitoring and endocrine substitution were rarely considered by respondents (31 and 35% of respondents, respectively). 98% of the respondents used crystalloids for fluid resuscitation. During the procedure, use of neuromuscular blockers, opioids and sedative agents were considered by respectively 84, 61 and 27% of the respondents. A very high level of agreement (10 [8-10], on a ten-points Likert-style scale) was reported concerning the expected impact of intraoperative anesthetic management on the primary function of grafts. CONCLUSIONS: Declared anesthetic practice appeared in accordance with guidelines concerning organ donor management in the ICU. Further studies are needed to evaluate the specific impact of intraoperative management during this procedure and thus the need for specific anesthetic guidelines.

Pheochromocytoma Crisis in the ICU: A French Multicenter Cohort Study With Emphasis on Rescue Extracorporeal Membrane Oxygenation.

OBJECTIVES: To describe the characteristics, management, and outcome of patients admitted to ICUs for pheochromocytoma crisis. DESIGN: A 16-year multicenter retrospective study. SETTING: Fifteen university and nonuniversity ICUs in France. PATIENTS: Patients admitted in ICU for pheochromocytoma crisis. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: We included 34 patients with a median age of 46 years (40-54 yr); 65% were males. At admission, the median Sequential Organ Failure Assessment score was 8 (4-12) and median Simplified Acute Physiology Score II 49.5 (27-70). The left ventricular ejection fraction was consistently decreased with a median value of 30% (15-40%). Mechanical ventilation was required in 23 patients, mainly because of congestive heart failure. Vasoactive drugs were used in 23 patients (68%) and renal replacement therapy in eight patients (24%). Extracorporeal membrane oxygenation was used as a rescue therapy in 14 patients (41%). Pheochromocytoma was diagnosed by CT in 33 of 34 patients. When assayed, urinary metanephrine and catecholamine levels were consistently elevated. Five patients underwent urgent surgery, including two during extracorporeal membrane oxygenation. Overall ICU mortality was 24% (8/34), and overall 90-day mortality was 27% (9/34). Crude 90-day mortality was not significantly different between patients managed with versus without extracorporeal membrane oxygenation (22% vs 30%) (p = 0.7) despite higher severity scores at admission in the extracorporeal membrane oxygenation group. CONCLUSIONS: Mortality is high in pheochromocytoma crisis. Routinely considering this diagnosis and performing abdominal CT in patients with unexplained cardiogenic shock may allow an earlier diagnosis. Extracorporeal membrane oxygenation and adrenalectomy should be considered as a therapeutic in most severe cases.

"It Was the Only Thing I Could Hold Onto, But ": Receiving a Letter of Condolence After Loss of a Loved One in the ICU: A Qualitative Study of Bereaved Relatives' Experience.

OBJECTIVES: Family members of patients who die in the ICU often remain with unanswered questions and suffer from lack of closure. A letter of condolence may help bereaved relatives, but little is known about their experience of receiving such a letter. The objective of the study was to understand bereaved family members' experience of receiving a letter of condolence. DESIGN: Qualitative study using interviews with bereaved family members who received a letter of condolence and letters written by these family members to the ICU team. This study was designed to provide insight into the results of a larger randomized, controlled, multicenter study. SETTING: Twenty-two ICUs in France. SUBJECTS: Family members who lost a loved one in the ICU and who received a letter of condolence. MEASUREMENTS AND MAIN RESULTS: Thematic analysis was used and was based on 52 interviews and 26 letters. Six themes emerged: 1) a feeling of support, 2) humanization of the medical system, 3) an opportunity for reflection, 4) an opportunity to describe their loved one, 5) continuity and closure, and 6) doubts and ambivalence. Possible difficulties emerged, notably the re-experience of the trauma, highlighting the absence of further support. CONCLUSIONS: This study describes the benefits of receiving a letter of condolence; mainly, it humanizes the medical institution (feeling of support, confirmation of the role played by the relative, supplemental information). However, this study also shows a common ambivalence about the letter of condolence's benefit. Healthcare workers must strive to adapt bereavement follow-up to each individual situation.

Video Laryngoscopy vs Direct Laryngoscopy on Successful First-Pass Orotracheal Intubation Among ICU Patients: A Randomized Clinical Trial.

Importance: In the intensive care unit (ICU), orotracheal intubation can be associated with increased risk of complications because the patient may be acutely unstable, requiring prompt intervention, often by a practitioner with nonexpert skills. Video laryngoscopy may decrease this risk by improving glottis visualization. Objective: To determine whether video laryngoscopy increases the frequency of successful first-pass orotracheal intubation compared with direct laryngoscopy in ICU patients. Design, Setting, and Participants: Randomized clinical trial of 371 adults requiring intubation while being treated at 7 ICUs in France between May 2015 and January 2016; there was 28 days of follow-up. Interventions: Intubation using a video laryngoscope (n = 186) or direct laryngoscopy (n = 185). All patients received general anesthesia. Main Outcomes and Measures: The primary outcome was the proportion of patients with successful first-pass intubation. The secondary outcomes included time to successful intubation and mild to moderate and severe life-threatening complications. Results: Among 371 randomized patients (mean [SD] age, 62.8 [15.8] years; 136 [36.7%] women), 371 completed the trial. The proportion of patients with successful first-pass intubation did not differ significantly between the video laryngoscopy and direct laryngoscopy groups (67.7% vs 70.3%; absolute difference, -2.5% [95% CI, -11.9% to 6.9%]; P = .60). The proportion of first-attempt intubations performed by nonexperts (primarily residents, n = 290) did not differ between the groups (84.4% with video laryngoscopy vs 83.2% with direct laryngoscopy; absolute difference 1.2% [95% CI, -6.3% to 8.6%]; P = .76). The median time to successful intubation was 3 minutes (range, 2 to 4 minutes) for both video laryngoscopy and direct laryngoscopy (absolute difference, 0 [95% CI, 0 to 0]; P = .95). Video laryngoscopy was not associated with life-threatening complications (24/180 [13.3%] vs 17/179 [9.5%] for direct laryngoscopy; absolute difference, 3.8% [95% CI, -2.7% to 10.4%]; P = .25). In post hoc analysis, video laryngoscopy was associated with severe life-threatening complications (17/179 [9.5%] vs 5/179 [2.8%] for direct laryngoscopy; absolute difference, 6.7% [95% CI, 1.8% to 11.6%]; P = .01) but not with mild to moderate life-threatening complications (10/181 [5.4%] vs 14/181 [7.7%]; absolute difference, -2.3% [95% CI, -7.4% to 2.8%]; P = .37). Conclusions and Relevance: Among patients in the ICU requiring intubation, video laryngoscopy compared with direct laryngoscopy did not improve first-pass orotracheal intubation rates and was associated with higher rates of severe life-threatening complications. Further studies are needed to assess the comparative effectiveness of these 2 strategies in different clinical settings and among operators with diverse skill levels. Trial Registration: clinicaltrials.gov Identifier: NCT02413723.

SARS-CoV-2 Transmission during High-Altitude Field Studies.

Grimm, Mirjam, Lucie Ziegler, Annina Seglias, Maamed Mademilov, Kamila Magdieva, Gulzada Mirzalieva, Aijan Taalaibekova, Simone Suter, Simon R. Schneider, Fiona Zoller, Vera Bissig, Lukas Reinhard, Meret Bauer, Julian Müller, Tanja L. Ulrich, Arcangelo F. Carta, Patrick R. Bader, Konstantinos Bitos, Aurelia E. Reiser, Benoit Champigneulle, Damira Ashyralieva, Philipp M. Scheiwiller, Silvia Ulrich, Talant M. Sooronbaev, Michael Furian, and Konrad E. Bloch. SARS-CoV-2 Transmission during High-Altitude Field Studies. High Alt Med Biol. 00:00-00, 2024. Background: Throughout the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic, virus transmission during clinical research was of concern. Therefore, during high-altitude field studies performed in 2021, we took specific COVID-19 precautions and investigated the occurrence of SARS-CoV-2 infection. Methods: From May to September 2021, we performed studies in patients with chronic obstructive pulmonary disease (COPD) and in healthy school-age children in Kyrgyzstan in high-altitude facilities at 3,100 m and 3,250 m and at 760 m. The various implemented COVID-19 safety measures included systematic SARS-CoV-2 rapid antigen testing (RAT). Main outcomes were SARS-CoV-2-RAT-positive rate among participants and staff at initial presentation (prevalence) and SARS-CoV-2-RAT-positive conversion during and within 10 days after studies (incidence). Results: Among 338 participants and staff, SARS-CoV-2-RAT-positive prevalence was 15 (4.4%). During mean ± SD duration of individual study participation of 3.1 ± 1.0 day and within 10 days, RAT-positive conversion occurred in 1/237(0.4%) participants. Among staff working in studies for 31.5 ± 29.3 days, SARS-CoV-2-RAT-positive conversion was 11/101(10.9%). In all 338 individuals involved in the studies over the course of 15.6 weeks, the median SARS-CoV-2-RAT-positive incidence was 0.00%/week (quartiles 0.00; 0.64). Over the same period, the median background incidence among the total Kyrgyz population of 6,636 million was 0.06%/week (0.03; 0.11), p = 0.013 (Wilcoxon rank sum test). Conclusions: Taking precautions by implementing specific safety measures, SARS-CoV-2 transmission during clinical studies was very rare, and the SARS-CoV-2 incidence among participants and staff was lower than that in the general population during the same period. The results are reassuring and may help in decision-making on the conduct of clinical research in similar settings.

Increased survival of cirrhotic patients with septic shock.

INTRODUCTION: The overall outcome of septic shock has been recently improved. We sought to determine whether this survival gain extends to the high-risk subgroup of patients with cirrhosis. METHODS: Cirrhotic patients with septic shock admitted to a medical intensive care unit (ICU) during two consecutive periods (1997-2004 and 2005-2010) were retrospectively studied. RESULTS: Forty-seven and 42 cirrhotic patients presented with septic shock in 1997-2004 and 2005-2010, respectively. The recent period differed from the previous one by implementation of adjuvant treatments of septic shock including albumin infusion as fluid volume therapy, low-dose glucocorticoids, and intensive insulin therapy. ICU and hospital survival markedly improved over time (40% in 2005-2010 vs. 17% in 1997-2004, P = 0.02 and 29% in 2005-2010 vs. 6% in 1997-2004, P = 0.009, respectively). Furthermore, this survival gain in the latter period was sustained for 6 months (survival rate 24% in 2005-2010 vs. 6% in 1997-2004, P = 0.06). After adjustment with age, the liver disease stage (Child-Pugh score), and the critical illness severity score (SOFA score), ICU admission between 2005 and 2010 remained an independent favorable prognostic factor (odds ratio (OR) 0.09, 95% confidence interval (CI) 0.02-0.4, P = 0.004). The stage of the underlying liver disease was also independently associated with hospital mortality (Child-Pugh score: OR 1.42 per point, 95% CI 1.06-1.9, P = 0.018). CONCLUSIONS: In the light of advances in management of both cirrhosis and septic shock, survival of such patients substantially increased over recent years. The stage of the underlying liver disease and the related therapeutic options should be included in the decision-making process for ICU admission.

Beyond the Lungs: O 2 Supplementation Improves Cerebral Oxygenation and Fatigue during Exercise in Interstitial Lung Disease.

PURPOSE: Cerebral hypoxia may exacerbate the perception of fatigue. We previously demonstrated that exercise-related hypoxemia, a hallmark of fibrotic interstitial lung disease ( f -ILD), dose dependently impairs cerebral oxygenation in these patients. It is unknown whether normalizing cerebral oxygenation with O 2 supplementation would be associated with positive changes in a relevant patient-centered outcome during exercise in f -ILD, such as improved perceived fatigue. METHODS: Fourteen patients (12 males, 72 ± 8 yr, 8 with idiopathic pulmonary fibrosis, lung diffusing capacity for carbon monoxide = 44% ± 13% predicted) performed a constant-load (60% peak work rate) cycle test to symptom limitation (Tlim) breathing medical air. Fourteen controls cycled up to Tlim of an age- and sex-matched patient. Patients repeated the test on supplemental O 2 (fraction of inspired O 2 = 0.41 ± 0.08) for the same duration. Near-infrared spectroscopy and the rating-of-fatigue (ROF) scale assessed prefrontal cortex oxygenation and perceived fatigue, respectively. RESULTS: Patients showed severe exertional hypoxemia (Tlim O 2 saturation by pulse oximetry = 80% ± 8%); they had poorer cerebral oxygenation (e.g., oxy-deoxyhemoglobin difference [HbDiff] = -3.5 ± 4.7 [range = -17.6 to +1.9] vs +1.9 ± 1.7 µmol from rest) and greater fatigue (ROF = 6.2 ± 2.0 vs 2.6 ± 2.3) versus controls under air ( P < 0.001). Reversal of exertional hypoxemia with supplemental O 2 led to improved HbDiff (+1.7 ± 2.4 µmol from rest; no longer differing from controls) and lower ROF scores (3.7 ± 1.2, P < 0.001 vs air) in patients. There was a significant correlation between O 2 -induced changes in HbDiff and ROF scores throughout exercise in f -ILD ( rrepeated-measures correlation = -0.51, P < 0.001). CONCLUSIONS: Supplemental O 2 improved cerebral oxygenation during exercise in f -ILD, which was moderately associated with lower ratings of perceived fatigue. Reversing cerebral hypoxia with O 2 supplementation may thus have positive effects on patients' disablement beyond those expected from lower ventilation and dyspnea in this patient population.

Hypoxia-altitude simulation test to predict altitude-related adverse health effects in COPD patients.

Background/aims: Amongst numerous travellers to high altitude (HA) are many with the highly prevalent COPD, who are at particular risk for altitude-related adverse health effects (ARAHE). We then investigated the hypoxia-altitude simulation test (HAST) to predict ARAHE in COPD patients travelling to altitude. Methods: This prospective diagnostic accuracy study included 75 COPD patients: 40 women, age 58±9 years, forced expiratory volume in 1 s (FEV1) 40-80% pred, oxygen saturation measured by pulse oximetry (S pO2 ) ≥92% and arterial carbon dioxide tension (P aCO2 ) <6 kPa. Patients underwent baseline evaluation and HAST, breathing normobaric hypoxic air (inspiratory oxygen fraction (F IO2 ) of 15%) for 15 min, at low altitude (760 m). Cut-off values for a positive HAST were set according to British Thoracic Society (BTS) guidelines (arterial oxygen tension (P aO2 ) <6.6 kPa and/or S pO2 <85%). The following day, patients travelled to HA (3100 m) for two overnight stays where ARAHE development including acute mountain sickness (AMS), Lake Louise Score ≥4 and/or AMS score ≥0.7, severe hypoxaemia (S pO2 <80% for >30 min or 75% for >15 min) or intercurrent illness was observed. Results: ARAHE occurred in 50 (66%) patients and 23 out of 75 (31%) were positive on HAST according to S pO2 , and 11 out of 64 (17%) according to P aO2 . For S pO2 /P aO2 we report a sensitivity of 46/25%, specificity of 84/95%, positive predictive value of 85/92% and negative predictive value of 44/37%. Conclusion: In COPD patients ascending to HA, ARAHE are common. Despite an acceptable positive predictive value of the HAST to predict ARAHE, its clinical use is limited by its insufficient sensitivity and overall accuracy. Counselling COPD patients before altitude travel remains challenging and best focuses on early recognition and treatment of ARAHE with oxygen and descent.

Validation of Noninvasive Assessment of Pulmonary Gas Exchange in Patients with Chronic Obstructive Pulmonary Disease during Initial Exposure to High Altitude.

Investigation of pulmonary gas exchange efficacy usually requires arterial blood gas analysis (aBGA) to determine arterial partial pressure of oxygen (mPaO2) and compute the Riley alveolar-to-arterial oxygen difference (A-aDO2); that is a demanding and invasive procedure. A noninvasive approach (AGM100), allowing the calculation of PaO2 (cPaO2) derived from pulse oximetry (SpO2), has been developed, but this has not been validated in a large cohort of chronic obstructive pulmonary disease (COPD) patients. Our aim was to conduct a validation study of the AG100 in hypoxemic moderate-to-severe COPD. Concurrent measurements of cPaO2 (AGM100) and mPaO2 (EPOC, portable aBGA device) were performed in 131 moderate-to-severe COPD patients (mean ±SD FEV1: 60 ± 10% of predicted value) and low-altitude residents, becoming hypoxemic (i.e., SpO2 < 94%) during a short stay at 3100 m (Too-Ashu, Kyrgyzstan). Agreements between cPaO2 (AGM100) and mPaO2 (EPOC) and between the O2-deficit (calculated as the difference between end-tidal pressure of O2 and cPaO2 by the AGM100) and Riley A-aDO2 were assessed. Mean bias (±SD) between cPaO2 and mPaO2 was 2.0 ± 4.6 mmHg (95% Confidence Interval (CI): 1.2 to 2.8 mmHg) with 95% limits of agreement (LoA): -7.1 to 11.1 mmHg. In multivariable analysis, larger body mass index (p = 0.046), an increase in SpO2 (p < 0.001), and an increase in PaCO2-PETCO2 difference (p < 0.001) were associated with imprecision (i.e., the discrepancy between cPaO2 and mPaO2). The positive predictive value of cPaO2 to detect severe hypoxemia (i.e., PaO2 ≤ 55 mmHg) was 0.94 (95% CI: 0.87 to 0.98) with a positive likelihood ratio of 3.77 (95% CI: 1.71 to 8.33). The mean bias between O2-deficit and A-aDO2 was 6.2 ± 5.5 mmHg (95% CI: 5.3 to 7.2 mmHg; 95%LoA: -4.5 to 17.0 mmHg). AGM100 provided an accurate estimate of PaO2 in hypoxemic patients with COPD, but the precision for individual values was modest. This device is promising for noninvasive assessment of pulmonary gas exchange efficacy in COPD patients.

The human blood transcriptome exhibits time-of-day-dependent response to hypoxia: Lessons from the highest city in the world.

High altitude exposes humans to hypobaric hypoxia, which induces various physiological and molecular changes. Recent studies point toward interaction between circadian rhythms and the hypoxic response, yet their human relevance is lacking. Here, we examine the effect of different high altitudes in conjunction with time of day on human whole-blood transcriptome upon an expedition to the highest city in the world, La Rinconada, Peru, which is 5,100 m above sea level. We find that high altitude vastly affects the blood transcriptome and, unexpectedly, does not necessarily follow a monotonic response to altitude elevation. Importantly, we observe daily variance in gene expression, especially immune-related genes, which is largely altitude dependent. Moreover, using a digital cytometry approach, we estimate relative changes in abundance of different cell types and find that the response of several immune cell types is time- and altitude dependent. Taken together, our data provide evidence for interaction between the transcriptional response to hypoxia and the time of day in humans.