Hyperinflammatory environment drives dysfunctional myeloid cell effector response to bacterial challenge in COVID-19.

COVID-19 displays diverse disease severities and symptoms including acute systemic inflammation and hypercytokinemia, with subsequent dysregulation of immune cells. Bacterial superinfections in COVID-19 can further complicate the disease course and are associated with increased mortality. However, there is limited understanding of how SARS-CoV-2 pathogenesis and hypercytokinemia impede the innate immune function against bacterial superinfections. We assessed the influence of COVID-19 plasma hypercytokinemia on the functional responses of myeloid immune cells upon bacterial challenges from acute-phase COVID-19 patients and their corresponding recovery-phase. We show that a severe hypercytokinemia status in COVID-19 patients correlates with the development of bacterial superinfections. Neutrophils and monocytes derived from COVID-19 patients in their acute-phase showed an impaired intracellular microbicidal capacity upon bacterial challenges. The impaired microbicidal capacity was reflected by abrogated MPO and reduced NETs production in neutrophils along with reduced ROS production in both neutrophils and monocytes. Moreover, we observed a distinct pattern of cell surface receptor expression on both neutrophils and monocytes, in line with suppressed autocrine and paracrine cytokine signaling. This phenotype was characterized by a high expression of CD66b, CXCR4 and low expression of CXCR1, CXCR2 and CD15 in neutrophils and low expression of HLA-DR, CD86 and high expression of CD163 and CD11b in monocytes. Furthermore, the impaired antibacterial effector function was mediated by synergistic effect of the cytokines TNF-α, IFN-γ and IL-4. COVID-19 patients receiving dexamethasone showed a significant reduction of overall inflammatory markers in the plasma as well as exhibited an enhanced immune response towards bacterial challenge ex vivo. Finally, broad anti-inflammatory treatment was associated with a reduction in CRP, IL-6 levels as well as length of ICU stay and ventilation-days in critically ill COVID-19 patients. Our data provides insights into the transient functional dysregulation of myeloid immune cells against subsequent bacterial infections in COVID-19 patients and describe a beneficial role for the use of dexamethasone in these patients.

The microcirculation in perioperative medicine: a narrative review.

The microcirculation describes the network of the smallest vessels in our cardiovascular system. On a microcirculatory level, oxygen delivery is determined by the flow of oxygen-carrying red blood cells in a given single capillary (capillary red blood cell flow) and the density of the capillary network in a given tissue volume (capillary vessel density). Handheld vital videomicroscopy enables visualisation of the capillary bed on the surface of organs and tissues but currently is only used for research. Measurements are generally possible on all organ surfaces but are most often performed in the sublingual area. In patients presenting for elective surgery, the sublingual microcirculation is usually intact and functional. Induction of general anaesthesia slightly decreases capillary red blood cell flow and increases capillary vessel density. During elective, even major, noncardiac surgery, the sublingual microcirculation is preserved and remains functional, presumably because elective noncardiac surgery is scheduled trauma and haemodynamic alterations are immediately treated by anaesthesiologists, usually restoring the macrocirculation before the microcirculation is substantially impaired. Additionally, surgery is regional trauma and thus likely causes regional, rather than systemic, impairment of the microcirculation. Whether or not the sublingual microcirculation is impaired after noncardiac surgery remains a subject of ongoing research. Similarly, it remains unclear if cardiac surgery, especially with cardiopulmonary bypass, impairs the sublingual microcirculation. The effects of therapeutic interventions specifically targeting the microcirculation remain to be elucidated and tested. Future research should focus on further improving microcirculation monitoring methods and investigating how regional microcirculation monitoring can inform clinical decision-making and treatment.

The effect of CO2 laser therapy on vaginal microcirculatory parameters in an animal model for genitourinary syndrome of menopause.

BACKGROUND: Vaginal laser therapy for the treatment of genitourinary syndrome of menopause (GSM) has been introduced to the market with limited (pre)clinical and experimental evidence supporting its efficacy. It is suggested that vaginal laser therapy increases epithelial thickness and improves vascularization, but the underlying biological working mechanism has not been substantiated yet. OBJECTIVE: To evaluate the effects of CO2 laser therapy on vaginal atrophy using noninvasive incident dark field (IDF) imaging in a large animal model for GSM. DESIGN, SETTING, AND PARTICIPANTS: An animal study was conducted between 2018 and 2019 and included 25 Dohne Merino ewes, of which 20 underwent bilateral ovariectomy (OVX) to induce iatrogenic menopause, and 5 did not. The total study duration was 10 months. INTERVENTIONS: Five months after OVX, ovariectomized ewes received monthly applications of CO2 laser (n = 7), vaginal estrogen (n = 7), or no treatment (n = 6) for 3 months. IDF imaging was performed monthly in all animals. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the proportion of image sequences containing capillary loops (angioarchitecture). Secondary outcomes included focal depth (epithelial thickness), and quantitative measures of vessel density and perfusion. Treatment effects were evaluated using ANCOVA and binary logistic regression. RESULTS AND LIMITATIONS: Compared to OVX-only, ewes treated with estrogen demonstrated a higher capillary loops proportion (4% vs. 75%, p < 0.01), and higher focal depth (60 (IQR 60-80) vs. 80 (IQR 80-80) p < 0.05). CO2 laser therapy did not change microcirculatory parameters. As the ewes' vaginal epithelium is thinner than that of humans, it may demand different laser settings. CONCLUSIONS: In a large animal model for GSM, CO2 laser therapy does not affect microcirculatory outcomes related to GSM, whereas vaginal estrogen treatment does. Until more homogeneous and objective evidence about its efficacy is available, CO2 laser therapy should not be adopted into widespread practice for treating GSM.

Morphologic Mapping of the Sublingual Microcirculation in Healthy Volunteers.

PURPOSE: Monitoring the sublingual and oral microcirculation (SM-OM) using hand-held vital microscopes (HVMs) has provided valuable insight into the (patho)physiology of diseases. However, the microvascular anatomy in a healthy population has not been adequately described yet. METHODS: Incident dark field-based HVM imaging was used to visualize the SM-OM. First, the SM was divided into four different fields; Field-a (between incisors-lingua), Field-b (between the canine-first premolar-lingua), Field-c (between the first-second premolar-lingua), Field-d (between the second molar-wisdom teeth-lingua). Second, we investigated the buccal area, lower and upper lip. Total/functional vessel density (TVD/FCD), focus depth (FD), small vessel mean diameters (SVMDs), and capillary tortuosity score (CTS) were compared between the areas. RESULTS: Fifteen volunteers with a mean age of 29 ± 6 years were enrolled. No statistical difference was found between the sublingual fields in terms of TVD (p = 0.30), FCD (p = 0.38), and FD (p = 0.09). SVMD was similar in Field-a, Field-b, and Field-c (p = 0.20-0.30), and larger in Field-d (p < 0.01, p = 0.015). The CTS of the buccal area was higher than in the lips. CONCLUSION: The sublingual area has a homogenous distribution in TVD, FCD, FD, and SVMD. This study can be a description of the normal microvascular anatomy for future researches regarding microcirculatory assessment.

Microcirculatory tissue perfusion during general anaesthesia and noncardiac surgery: An observational study using incident dark field imaging with automated video analysis.

BACKGROUND: Handheld vital microscopy allows direct observation of red blood cells within the sublingual microcirculation. Automated analysis allows quantifying microcirculatory tissue perfusion variables - including tissue red blood cell perfusion (tRBCp), a functional variable integrating microcirculatory convection and diffusion capacities. OBJECTIVE: We aimed to describe baseline microcirculatory tissue perfusion in patients presenting for elective noncardiac surgery and test that microcirculatory tissue perfusion is preserved during elective general anaesthesia for noncardiac surgery. DESIGN: Prospective observational study. SETTING: University Medical Center Hamburg-Eppendorf, Hamburg, Germany. PATIENTS: 120 elective noncardiac surgery patients (major abdominal, orthopaedic or trauma and minor urologic surgery) and 40 young healthy volunteers. MAIN OUTCOME MEASURES: We measured sublingual microcirculation using incident dark field imaging with automated analysis at baseline before induction of general anaesthesia, under general anaesthesia before surgical incision and every 30 min during surgery. We used incident the dark field imaging technology with a validated automated analysis software. RESULTS: A total of 3687 microcirculation video sequences were analysed. Microcirculatory tissue perfusion variables varied substantially between individuals - but ranges were similar between patients and volunteers. Under general anaesthesia before surgical incision, there were no important changes in tRBCp, functional capillary density and capillary haematocrit compared with preinduction baseline. However, total vessel density was higher and red blood cell velocity and the proportion of perfused vessels were lower under general anaesthesia. There were no important changes in any microcirculatory tissue perfusion variables during surgery. CONCLUSION: In patients presenting for elective noncardiac surgery, baseline microcirculatory tissue perfusion variables vary substantially between individuals - but ranges are similar to those in young healthy volunteers. Microcirculatory tissue perfusion is preserved during general anaesthesia and noncardiac surgery - when macrocirculatory haemodynamics are maintained.

Capillary Leukocytes, Microaggregates, and the Response to Hypoxemia in the Microcirculation of Coronavirus Disease 2019 Patients.

OBJECTIVES: In this study, we hypothesized that coronavirus disease 2019 patients exhibit sublingual microcirculatory alterations caused by inflammation, coagulopathy, and hypoxemia. DESIGN: Multicenter case-controlled study. SETTING: Two ICUs in The Netherlands and one in Switzerland. PATIENTS: Thirty-four critically ill coronavirus disease 2019 patients were compared with 33 healthy volunteers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The microcirculatory parameters quantified included total vessel density (mm × mm-2), functional capillary density (mm × mm-2), proportion of perfused vessels (%), capillary hematocrit (%), the ratio of capillary hematocrit to systemic hematocrit, and capillary RBC velocity (µm × s-1). The number of leukocytes in capillary-postcapillary venule units per 4-second image sequence (4 s-1) and capillary RBC microaggregates (4 s-1) was measured. In comparison with healthy volunteers, the microcirculation of coronavirus disease 2019 patients showed increases in total vessel density (22.8 ± sd 5.1 vs 19.9 ± 3.3; p < 0.0001) and functional capillary density (22.2 ± 4.8 vs 18.8 ± 3.1; p < 0.002), proportion of perfused vessel (97.6 ± 2.1 vs 94.6 ± 6.5; p < 0.01), RBC velocity (362 ± 48 vs 306 ± 53; p < 0.0001), capillary hematocrit (5.3 ± 1.3 vs 4.7 ± 0.8; p < 0.01), and capillary-hematocrit-to-systemic-hematocrit ratio (0.18 ± 0.0 vs 0.11 ± 0.0; p < 0.0001). These effects were present in coronavirus disease 2019 patients with Sequential Organ Failure Assessment scores less than 10 but not in patients with Sequential Organ Failure Assessment scores greater than or equal to 10. The numbers of leukocytes (17.6 ± 6.7 vs 5.2 ± 2.3; p < 0.0001) and RBC microaggregates (0.90 ± 1.12 vs 0.06 ± 0.24; p < 0.0001) was higher in the microcirculation of the coronavirus disease 2019 patients. Receiver-operating-characteristics analysis of the microcirculatory parameters identified the number of microcirculatory leukocytes and the capillary-hematocrit-to-systemic-hematocrit ratio as the most sensitive parameters distinguishing coronavirus disease 2019 patients from healthy volunteers. CONCLUSIONS: The response of the microcirculation to coronavirus disease 2019-induced hypoxemia seems to be to increase its oxygen-extraction capacity by increasing RBC availability. Inflammation and hypercoagulation are apparent in the microcirculation by increased numbers of leukocytes and RBC microaggregates.

Automated quantification of tissue red blood cell perfusion as a new resuscitation target.

PURPOSE OF REVIEW: Identification of insufficient tissue perfusion is fundamental to recognizing circulatory shock in critically ill patients, and the primary target to restore adequate oxygen delivery. However, the concept of tissue perfusion remains ill-defined and out-of-reach for clinicians as point-of-care resuscitation target. Even though handheld vital microscopy (HVM) provides the technical prerequisites to collect information on tissue perfusion in the sublingual microcirculation, challenges in image analysis prevent quantification of tissue perfusion and manual analysis steps prohibit point-of-care application. The present review aims to discuss recent advances in algorithm-based HVM analysis and the physiological basis of tissue perfusion-based resuscitation parameters. RECENT FINDINGS: Advanced computer vision algorithm such as MicroTools independently quantify microcirculatory diffusion and convection capacity by HVM and provide direct insight into tissue perfusion, leading to our formulation a functional parameter, tissue red blood cell (RBC) perfusion (tRBCp). Its definition is discussed in terms of the physiology of oxygen transport to the tissue and its expected effect as a point-of-care resuscitation target. Further refinements to microcirculatory monitoring include multiwavelength HVM techniques and maximal recruitable microcirculatory diffusion and convection capacity. SUMMARY: tRBCp as measured using algorithm-based HVM analysis with an automated software called MicroTools, represents a promising candidate to assess microcirculatory delivery of oxygen for microcirculation-based resuscitation in critically ill patients at the point-of-care.

ECCO2R therapy in the ICU: consensus of a European round table meeting.

BACKGROUND: With recent advances in technology, patients with acute respiratory distress syndrome (ARDS) and severe acute exacerbations of chronic obstructive pulmonary disease (ae-COPD) could benefit from extracorporeal CO2 removal (ECCO2R). However, current evidence in these indications is limited. A European ECCO2R Expert Round Table Meeting was convened to further explore the potential for this treatment approach. METHODS: A modified Delphi-based method was used to collate European experts' views to better understand how ECCO2R therapy is applied, identify how patients are selected and how treatment decisions are made, as well as to identify any points of consensus. RESULTS: Fourteen participants were selected based on known clinical expertise in critical care and in providing respiratory support with ECCO2R or extracorporeal membrane oxygenation. ARDS was considered the primary indication for ECCO2R therapy (n = 7), while 3 participants considered ae-COPD the primary indication. The group agreed that the primary treatment goal of ECCO2R therapy in patients with ARDS was to apply ultra-protective lung ventilation via managing CO2 levels. Driving pressure (≥ 14 cmH2O) followed by plateau pressure (Pplat; ≥ 25 cmH2O) was considered the most important criteria for ECCO2R initiation. Key treatment targets for patients with ARDS undergoing ECCO2R included pH (> 7.30), respiratory rate (< 25 or < 20 breaths/min), driving pressure (< 14 cmH2O) and Pplat (< 25 cmH2O). In ae-COPD, there was consensus that, in patients at risk of non-invasive ventilation (NIV) failure, no decrease in PaCO2 and no decrease in respiratory rate were key criteria for initiating ECCO2R therapy. Key treatment targets in ae-COPD were patient comfort, pH (> 7.30-7.35), respiratory rate (< 20-25 breaths/min), decrease of PaCO2 (by 10-20%), weaning from NIV, decrease in HCO3- and maintaining haemodynamic stability. Consensus was reached on weaning protocols for both indications. Anticoagulation with intravenous unfractionated heparin was the strategy preferred by the group. CONCLUSIONS: Insights from this group of experienced physicians suggest that ECCO2R therapy may be an effective supportive treatment for adults with ARDS or ae-COPD. Further evidence from randomised clinical trials and/or high-quality prospective studies is needed to better guide decision making.

Microcirculation: Physiology, Pathophysiology, and Clinical Application.

This paper briefly reviews the physiological components of the microcirculation, focusing on its function in homeostasis and its central function in the realization of oxygen transport to tissue cells. Its pivotal role in the understanding of circulatory compromise in states of shock and renal compromise is discussed. Our introduction of hand-held vital microscopes (HVM) to clinical medicine has revealed the importance of the microcirculation as a central target organ in states of critical illness and inadequate response to therapy. Technical and methodological developments have been made in hardware and in software including our recent introduction and validation of automatic analysis software called MicroTools, which now allows point-of-care use of HVM imaging at the bedside for instant availability of functional microcirculatory parameters needed for microcirculatory targeted resuscitation procedures to be a reality.

Effect of Polyethylene-glycolated Carboxyhemoglobin on Renal Microcirculation in a Rat Model of Hemorrhagic Shock.

BACKGROUND: Primary resuscitation fluid to treat hemorrhagic shock remains controversial. Use of hydroxyethyl starches raised concerns of acute kidney injury. Polyethylene-glycolated carboxyhemoglobin, which has carbon monoxide-releasing molecules and oxygen-carrying properties, was hypothesized to sustain cortical renal microcirculatory PO2 after hemorrhagic shock and reduce kidney injury. METHODS: Anesthetized and ventilated rats (n = 42) were subjected to pressure-controlled hemorrhagic shock for 1 h. Renal cortical PO2 was measured in exposed kidneys using a phosphorescence quenching method. Rats were randomly assigned to six groups: polyethylene-glycolated carboxyhemoglobin 320 mg · kg, 6% hydroxyethyl starch (130/0.4) in Ringer's acetate, blood retransfusion, diluted blood retransfusion (~4 g · dl), nonresuscitated animals, and time control. Nitric oxide and heme oxygenase 1 levels were determined in plasma. Kidney immunohistochemistry (histologic scores of neutrophil gelatinase-associated lipocalin and tumor necrosis factor-α) and tubular histologic damages analyses were performed. RESULTS: Blood and diluted blood restored renal PO2 to 51 ± 5 mmHg (mean difference, -18; 95% CI, -26 to -11; P < 0.0001) and 47 ± 5 mmHg (mean difference, -23; 95% CI, -31 to -15; P < 0.0001), respectively, compared with 29 ± 8 mmHg for hydroxyethyl starch. No differences between polyethylene-glycolated carboxyhemoglobin and hydroxyethyl starch were observed (33 ± 7 mmHg vs. 29 ± 8 mmHg; mean difference, -5; 95% CI, -12 to 3; P = 0.387), but significantly less volume was administered (4.5 [3.3-6.2] vs. 8.5[7.7-11.4] ml; mean rank difference, 11.98; P = 0.387). Blood and diluted blood increased the plasma bioavailability of nitric oxide compared with hydroxyethyl starch (mean rank difference, -20.97; P = 0.004; and -17.13; P = 0.029, respectively). No changes in heme oxygenase 1 levels were observed. Polyethylene-glycolated carboxyhemoglobin limited tubular histologic damages compared with hydroxyethyl starch (mean rank difference, 60.12; P = 0.0012) with reduced neutrophil gelatinase-associated lipocalin (mean rank difference, 84.43; P < 0.0001) and tumor necrosis factor-α (mean rank difference, 49.67; P = 0.026) histologic scores. CONCLUSIONS: Polyethylene-glycolated carboxyhemoglobin resuscitation did not improve renal PO2 but limited tubular histologic damages and neutrophil gelatinase-associated lipocalin upregulation after hemorrhage compared with hydroxyethyl starch, whereas a lower volume was required to sustain macrocirculation.

Carotid chemoreceptor control of muscle sympathetic nerve activity in hypobaric hypoxia.

NEW FINDINGS: What is the central question of this study? High-altitude hypoxia increases muscle sympathetic nerve activity (MSNA), but whether intravenous infusion of dopamine, to blunt the responsiveness of the carotid chemoreceptors, reduces MSNA at high altitude is not known. What is the main finding and its importance? Muscle sympathetic nerve activity was elevated after 15-17 days of high-altitude hypoxia (3454 m) compared with values at 'sea level' (432 m). However, intravenous dopamine infusion to blunt the responsiveness of the carotid chemoreceptors did not significantly decrease MSNA either at sea level or at high altitude, suggesting that high-altitude sympathoexcitation arises via a different mechanism. High-altitude hypoxia causes pronounced sympathoexcitation, but the underlying mechanisms remain unclear. We tested the hypothesis that i.v. infusion of dopamine to attenuate carotid chemoreceptor responsiveness would reduce muscle sympathetic nerve activity (MSNA) at high altitude. Nine healthy individuals [mean (SD); 26 (4) years of age] were studied at 'sea level' (SL; Zurich) and at high altitude (ALT; 3454 m; 15-17 days after arrival), both while breathing the ambient air and during an acute incremental hypoxia test (eight 3 min stages; partial pressure of end-tidal O2 90-45 mmHg). Intravenous infusions of dopamine (3 µg kg-1  min-1 ) and placebo (saline) were administered on both study days, according to a single-blind randomized cross-over design. Sojourn to high altitude decreased the partial pressure of end-tidal O2 (to ∼60 mmHg) and increased minute ventilation [V̇E; mean ± SEM, SL versus ALT: saline, 8.6 ± 0.5 versus 11.3 ± 0.6 l min-1 ; dopamine, 8.2 ± 0.5 versus 10.6 ± 0.8 l min-1 ; P < 0.05] and MSNA burst frequency by ∼80% [SL versus ALT: saline, 16 ± 3 versus 28 ± 4 bursts min-1 ; dopamine, 16 ± 4 versus 31 ± 4 bursts min-1 ; P < 0.05) when breathing the ambient air, but were not different with dopamine. Increases in MSNA burst frequency and V̇E during the acute incremental hypoxia test were greater at ALT than SL (P < 0.05). Dopamine did not affect the magnitude of the MSNA burst frequency response to acute incremental hypoxia at either SL or ALT. However, V̇E was lower with dopamine than saline administration throughout the acute incremental hypoxia test at ALT. These data indicate that i.v. infusion of low-dose dopamine to blunt the responsiveness of the carotid chemoreceptors does not significantly decrease MSNA at high altitude.

Parasympathetic withdrawal increases heart rate after 2 weeks at 3454 m altitude.

KEY POINTS: Heart rate is increased in chronic hypoxia and we tested whether this is the result of increased sympathetic nervous activity, reduced parasympathetic nervous activity, or a non-autonomic mechanism. In seven lowlanders, heart rate was measured at sea level and after 2 weeks at high altitude after individual and combined pharmacological inhibition of sympathetic and/or parasympathetic control of the heart. Inhibition of parasympathetic control of the heart alone or in combination with inhibition of sympathetic control abolished the high altitude-induced increase in heart rate. Inhibition of sympathetic control of the heart alone did not prevent the high altitude-induced increase in heart rate. These results indicate that a reduced parasympathetic nervous activity is the main mechanism underlying the elevated heart rate in chronic hypoxia. ABSTRACT: Chronic hypoxia increases resting heart rate (HR), but the underlying mechanism remains incompletely understood. We investigated the relative contributions of the sympathetic and parasympathetic nervous systems, along with potential non-autonomic mechanisms, by individual and combined pharmacological inhibition of muscarinic and/or ß-adrenergic receptors. In seven healthy lowlanders, resting HR was determined at sea level (SL) and after 15-18 days of exposure to 3454 m high altitude (HA) without drug intervention (control, CONT) as well as after intravenous administration of either propranolol (PROP), or glycopyrrolate (GLYC), or PROP and GLYC in combination (PROP+GLYC). Circulating noradrenaline concentration increased from 0.9 ± 0.4 nmol l-1 at SL to 2.7 ± 1.5 nmol l-1 at HA (P = 0.03). The effect of HA on HR depended on the type of autonomic inhibition (P = 0.006). Specifically, HR was increased at HA from 64 ± 10 to 74 ± 12 beats min-1 during the CONT treatment (P = 0.007) and from 52 ± 4 to 59 ± 5 beats min-1 during the PROP treatment (P < 0.001). In contrast, HR was similar between SL and HA during the GLYC treatment (110 ± 7 and 112 ± 5 beats min-1 , P = 0.28) and PROP+GLYC treatment (83 ± 5 and 85 ± 5 beats min-1 , P = 0.25). Our results identify a reduction in cardiac parasympathetic activity as the primary mechanism underlying the elevated HR associated with 2 weeks of exposure to hypoxia. Unexpectedly, the sympathoactivation at HA that was evidenced by increased circulating noradrenaline concentration had little effect on HR, potentially reflecting down-regulation of cardiac ß-adrenergic receptor function in chronic hypoxia. These effects of chronic hypoxia on autonomic control of the heart may concern not only HA dwellers, but also patients with disorders that are associated with hypoxaemia.

Twenty-eight days of exposure to 3454 m increases mitochondrial volume density in human skeletal muscle.

The role of hypoxia on skeletal muscle mitochondria is controversial. Studies superimposing exercise training on hypoxic exposure demonstrate an increase in skeletal muscle mitochondrial volume density (Mito(VD)) over equivalent normoxic training. In contrast, reductions in both skeletal muscle mass and Mito(VD) have been reported following mountaineering expeditions. These observations may, however, be confounded by negative energy balance, which may obscure the results. Accordingly we sought to examine the effects of high altitude hypoxic exposure on mitochondrial characteristics, with emphasis on Mito(VD), while minimizing changes in energy balance. For this purpose, skeletal muscle biopsies were obtained from nine lowlanders at sea level (Pre) and following 7 and 28 days of exposure to 3454 m. Maximal ergometer power output, whole body weight and composition, leg lean mass and skeletal muscle fibre area all remained unchanged following the altitude exposure. Transmission electron microscopy determined that intermyofibrillar (IMF) Mito(VD) was augmented (P = 0.028) by 11.5 ± 9.2% from Pre (5.05 ± 0.9%) to 28 Days (5.61 ± 0.04%). In contrast, there was no change in subsarcolemmal (SS) Mito(VD). As a result, total Mito(VD) (IMF + SS) was increased (P = 0.031) from 6.20 ± 1.5% at Pre to 6.62 ± 1.4% at 28 Days (7.8 ± 9.3%). At the same time no changes in mass-specific respiratory capacities, mitochondrial protein or antioxidant content were found. This study demonstrates that skeletal muscle Mito(VD) may increase with 28 days acclimation to 3454 m.

Heat training increases exercise capacity in hot but not in temperate conditions: a mechanistic counter-balanced cross-over study.

The aim was to determine the mechanisms facilitating exercise performance in hot conditions following heat training. In a counter-balanced order, seven males (V̇o2max 61.2 ± 4.4 ml·min(-1)·kg(-1)) were assigned to either 10 days of 90-min exercise training in 18 or 38°C ambient temperature (30% relative humidity) applying a cross-over design. Participants were tested for V̇o2max and 30-min time trial performance in 18 (T18) and 38°C (T38) before and after training. Blood volume parameters, sweat output, cardiac output (Q̇), cerebral perfusion (i.e., middle cerebral artery velocity [MCAvmean]), and other variables were determined. Before one set of exercise tests in T38, blood volume was acutely expanded by 538 ± 16 ml with an albumin solution (T38A) to determine the role of acclimatization induced hypervolemia on exercise performance. We furthermore hypothesized that heat training would restore MCAvmean and thereby limit centrally mediated fatigue. V̇o2max and time trial performance were equally reduced in T38 and T38A (7.2 ± 1.6 and 9.3 ± 2.5% for V̇o2max; 12.8 ± 2.8 and 12.9 ± 2.8% for time trial). Following heat training both were increased in T38 (9.6 ± 2.1 and 10.4 ± 3.1%, respectively), whereas both V̇o2max and time trial performance remained unchanged in T18. As expected, heat training augmented plasma volume (6 ± 2%) and mean sweat output (26 ± 6%), whereas sweat [Na(+)] became reduced by 19 ± 7%. In T38 Q̇max remained unchanged before (21.3 ± 0.6 l/min) to after (21.7 ± 0.5 l/min) training, whereas MCAvmean was increased by 13 ± 10%. However, none of the observed adaptations correlated with the concomitant observed changes in exercise performance.

Age, aerobic fitness, and cerebral perfusion during exercise: role of carbon dioxide.

Middle cerebral artery mean velocity (MCAvmean) is attenuated with increasing age both at rest and during exercise. The aim of this study was to determine the influence of the age-dependent reduction in arterial Pco2 (PaCO2) and physical fitness herein. We administered supplemental CO2 (CO2 trial) or no additional gas (control trial) to the inspired air in a blinded and randomized manner, and assessed middle cerebral artery mean flow velocity during graded exercise in 1) 21 young [Y; age 24 ± 3 yr (±SD)] volunteers of whom 11 were trained (YT) and 10 considered untrained (YUT), and 2) 17 old (O; 66 ± 4 yr) volunteers of whom 8 and 9 were considered trained (OT) and untrained (OUT), respectively. A resting hypercapnic reactivity test was also performed. MCAvmean and PaCO2 were lower in O [44.9 ± 3.1 cm/s and 30 ± 1 mmHg (±SE)] compared with Y (59.3 ± 2.3 cm/s and 34 ± 1 mmHg, P < 0.01) at rest, independent of aerobic fitness level. The age-related decreases in MCAvmean and PaCO2 persisted during exercise. Supplemental CO2 reduced the age-associated decline in MCAvmean by 50%, suggesting that PaCO2 is a major component in the decline. On the other hand, relative hypercapnic reactivity was neither influenced by age (P = 0.46) nor aerobic fitness (P = 0.36). Although supplemental CO2 attenuated exercise-induced reduction in cerebral oxygenation (near-infrared spectroscopy), this did not influence exercise performance. In conclusion, PaCO2 contributes to the age-associated decline in MCAvmean at rest and during exercise; however exercise capacity did not diminish this age effect.

Nitroglycerin challenge identifies microcirculatory target for improved resuscitation in patients with circulatory shock.

BACKGROUND: Circulatory shock and multi-organ failure remain major contributors to morbidity and mortality in critically ill patients and are associated with insufficient oxygen availability in the tissue. Intrinsic mechanisms to improve tissue perfusion, such as up-regulation of functional capillary density (FCD) and red blood cell velocity (RBCv), have been identified as maneuvers to improve oxygen extraction by the tissues; however, their role in circulatory shock and potential use as resuscitation targets remains unknown. To fill this gap, we examined the baseline and maximum recruitable FCD and RBCv in response to a topical nitroglycerin stimulus (FCDNG, RBCvNG) in patients with and without circulatory shock to test whether this may be a method to identify the presence and magnitude of a microcirculatory reserve capacity important for identifying a resuscitation target. METHODS: Sublingual handheld vital microscopy was performed after initial resuscitation in mechanically ventilated patients consecutively admitted to a tertiary medical ICU. FCD and RBCv were quantified using an automated computer vision algorithm (MicroTools). Patients with circulatory shock were retrospectively identified via standardized hemodynamic and clinical criteria and compared to patients without circulatory shock. RESULTS: 54 patients (57 ± 14y, BMI 26.3 ± 4.9 kg/m2, SAPS 56 ± 19, 65% male) were included, 13 of whom presented with circulatory shock. Both groups had similar cardiac index, mean arterial pressure, RBCv, and RBCvNG. Heart rate (p < 0.001), central venous pressure (p = 0.02), lactate (p < 0.001), capillary refill time (p < 0.01), and Mottling score (p < 0.001) were higher in circulatory shock after initial resuscitation, while FCD and FCDNG were 10% lower (16.9 ± 4.2 and 18.9 ± 3.2, p < 0.01; 19.3 ± 3.1 and 21.3 ± 2.9, p = 0.03). Nitroglycerin response was similar in both groups, and circulatory shock patients reached FCDNG similar to baseline FCD found in patients without shock. CONCLUSION: Critically ill patients suffering from circulatory shock were found to present with a lower sublingual FCD. The preserved nitroglycerin response suggests a dysfunction of intrinsic regulation mechanisms to increase the microcirculatory oxygen extraction capacity associated with circulatory shock and identifies a potential resuscitation target. These differences in microcirculatory hemodynamic function between patients with and without circulatory shock were not reflected in blood pressure or cardiac index.

The physiological basis for individualized oxygenation targets in critically ill patients with circulatory shock.

BACKGROUND: Circulatory shock, defined as decreased tissue perfusion, leading to inadequate oxygen delivery to meet cellular metabolic demands, remains a common condition with high morbidity and mortality. Rapid restitution and restoration of adequate tissue perfusion are the main treatment goals. To achieve this, current hemodynamic strategies focus on adjusting global physiological variables such as cardiac output (CO), hemoglobin (Hb) concentration, and arterial hemoglobin oxygen saturation (SaO2). However, it remains a challenge to identify optimal targets for these global variables that best support microcirculatory function. Weighting up the risks and benefits is especially difficult for choosing the amount of oxygen supplementation in critically ill patients. This review assesses the physiological basis for oxygen delivery to the tissue and provides an overview of the relevant literature to emphasize the importance of considering risks and benefits and support decision making at the bedside. PHYSIOLOGICAL PREMISES: Oxygen must reach the tissue to enable oxidative phosphorylation. The human body timely detects hypoxia via different mechanisms aiming to maintain adequate tissue oxygenation. In contrast to the pulmonary circulation, where the main response to hypoxia is arteriolar vasoconstriction, the regulatory mechanisms of the systemic circulation aim to optimize oxygen availability in the tissues. This is achieved by increasing the capillary density in the microcirculation and the capillary hematocrit thereby increasing the capacity of oxygen diffusion from the red blood cells to the tissue. Hyperoxia, on the other hand, is associated with oxygen radical production, promoting cell death. CURRENT STATE OF RESEARCH: Clinical trials in critically ill patients have primarily focused on comparing macrocirculatory endpoints and outcomes based on stroke volume and oxygenation targets. Some earlier studies have indicated potential benefits of conservative oxygenation. Recent trials show contradictory results regarding mortality, organ dysfunction, and ventilatory-free days. Empirical studies comparing various targets for SaO2, or partial pressure of oxygen indicate a U-shaped curve balancing positive and negative effects of oxygen supplementation. CONCLUSION AND FUTURE DIRECTIONS: To optimize risk-benefit ratio of resuscitation measures in critically ill patients with circulatory shock in addition to individual targets for CO and Hb concentration, a primary aim should be to restore tissue perfusion and avoid hyperoxia. In the future, an individualized approach with microcirculatory targets will become increasingly relevant. Further studies are needed to define optimal targets.

Microcirculatory Monitoring in Children with Congenital Heart Disease Before and After Cardiac Surgery.

In this prospective observational study, we investigated whether congenital heart disease (CHD) affects the microcirculation and whether the microcirculation is altered following cardiac surgery with cardiopulmonary bypass (CPB). Thirty-eight children with CHD undergoing cardiac surgery with CPB and 35 children undergoing elective, non-cardiac surgery were included. Repeated non-invasive sublingual microcirculatory measurements were performed with handheld vital microscopy. Before surgery, children with CHD showed similar perfused vessel densities and red blood cell velocities (RBCv) but less perfused vessels (p < 0.001), lower perfusion quality (p < 0.001), and higher small vessel densities (p = 0.039) than children without CHD. After cardiac surgery, perfused vessel densities and perfusion quality of small vessels declined (p = 0.025 and p = 0.032), while RBCv increased (p = 0.032). We demonstrated that CHD was associated with decreased microcirculatory perfusion and increased capillary recruitment. The microcirculation was further impaired after cardiac surgery. Decreased microcirculatory perfusion could be a warning sign for altered tissue oxygenation and requires further exploration.

Artificial intelligence in intensive care: moving towards clinical decision support systems.

The high complexity of care in the Intensive Care Unit environment has led, in the last decades, to a big effort in term of the improvement of patient's monitoring devices, increase of diagnostic and therapeutic opportunities, and development of electronic health records. Such advancements have enabled an increasing availability of large amounts of data that were supposed to provide more insight and understanding regarding pathophysiological processes and patient's prognosis providing useful tools able to support physicians in the clinical decision-making process. On the contrary, the interpolation, analysis, and interpretation of a such big amount of data has soon proven to be much more complicated than expected, opening the way for the development of tools based on machine learning (ML) algorithms. However, at the present, most of the AI-based algorithms developed in intensive care do not reach beyond the prototyping and development environment and are still far from being able to assist physicians at the bedside in the clinical decisions to improve quality and efficiency of care. The present review aimed to provide an overview of the status of ML-based algorithms in intensive care, to explore the concept of digital transformation, and to highlight possible next steps necessary to move towards a routine use of ML-based clinical decision support systems at the bedside. Finally, we described our attempt to apply the pillars of digital transformation in the field of microcirculation monitoring with the creation of the Microcirculation Network Research Group (MNRG).