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Dynamic cerebral autoregulation is often assessed by continuously recorded arterial blood pressure (ABP) and transcranial Doppler-derived mean cerebral blood flow velocity followed by analysis in the time and frequency domain, respectively. Sequential correlation (in the time domain, yielding e.g., the measure mean flow index, Mxa) and transfer function analysis (TFA) (in the frequency domain, yielding, e.g., normalised and non-normalised gain as well as phase in the low frequency domain) are commonly used approaches. This study investigated the diagnostic and prognostic performance of these metrics. We included recordings from 48 healthy volunteers, 19 patients with sepsis, 36 with traumatic brain injury (TBI), and 14 patients admitted to a neurorehabilitation unit. The diagnostic (between healthy volunteers and patients) and prognostic performance (to predict death or poor functional outcome) of Mxa and the TFA measures were assessed by area under the receiver-operating characteristic (AUROC) curves. AUROC curves generally indicated that the measures were ‘no better than chance’ (AUROC ∼0.5) both for distinguishing between healthy volunteers and patient groups, and for predicting outcomes in our cohort. No metric emerged as superior for distinguishing between healthy volunteers and different patient groups, for assessing the effect of interventions, or for predicting mortality or functional outcome.

BACKGROUND: Intensive care unit (ICU) patients with Coronavirus disease 2019 (COVID-19) have an increased risk of thromboembolic complications. We describe the occurrence of thromboembolic and bleeding events in all ICU patients with COVID-19 in Denmark during the first and second waves of the pandemic.METHODS: This was a sub-study of the Danish Intensive Care Covid database, in which all patients with SARS-CoV-2 admitted to Danish ICUs from 10th March 2020 to 30th June 2021 were included. We registered coagulation variables at admission, and all thromboembolic and bleeding events, and the use of heparins during ICU stay. Variables associated with thrombosis and bleeding and any association with 90-day mortality were estimated using Cox regression analyses.RESULTS: We included 1369 patients in this sub-study; 158 (12%, 95% confidence interval 10-13) had a thromboembolic event in ICU and 309 (23%, 20-25) had a bleeding event, among whom 81 patients (6%, 4.8-7.3) had major bleeding. We found that mechanical ventilation and increased D-dimer were associated with thrombosis and mechanical ventilation, low platelet count and presence of haematological malignancy were associated with bleeding. Most patients (76%) received increased doses of thromboprophylaxis during their ICU stay. Thromboembolic events were not associated with mortality in adjusted analysis (hazard ratio 1.35 [0.91-2.01, p = .14], whereas bleeding events were 1.55 [1.18-2.05, p = .002]).CONCLUSIONS: Both thromboembolic and bleeding events frequently occurred in ICU patients with COVID-19. Based on these data, it is not apparent that increased doses of thromboprophylaxis were beneficial.

Local immunopathogenesis of COVID-19 acute respiratory distress syndrome (CARDS) and the effects of systemic dexamethasone (DXM) treatment on pulmonary immunity in COVID-19 remain insufficiently understood. To provide further insight into insight into immune regulatory mechanisms in the lungs of CARDS (with and without DXM treatment) and critically ill non-COVID-19 patients (without DXM treatment), transcriptomic RNA-seq analysis of bronchoalveolar lavage fluid (BALF) was performed in these patients. Functional analysis was performed using gene ontology and a blood transcription module, and gene expression of select pro-inflammatory cytokines, interferon-stimulated genes (ISGs) and auto-IFN antibodies were assessed. We found 550 and 2173 differentially expressed genes in patients with non-DXM-CARDS and DXM-CARDS, respectively. DXM-CARDS was characterized by upregulation of genes related to pulmonary innate and adaptive immunity, notably B-cell and complement pathway activation, antigen presentation, phagocytosis and FC-gamma receptor signalling. Pro-inflammatory genes were not differentially expressed in CARDS vs. non-COVID-19, nor did they differ according to DXM. Most ISGs were specifically upregulated in CARDS, particularly in non-DXM-CARDS. Auto-IFN autoantibodies were detectable in BALF of some CARDS patients. In conclusion, DXM treatment was not associated with regulation of pro-inflammatory pathways in CARDS but with regulation of other specific local innate and adaptive immune responses.summaryThis study identifies differentially expressed genes in bronchoalveolar fluid of COVID-19 acute respiratory distress patients with a distinct RNA expression profile of those treated with dexamethasone. These results challenge the concept of a COVID-19 specific cytokine storm.

New findings What is the topic of this review? The use of proning for improving pulmonary gas exchange in critically ill patients. What advances does it highlight? Proning places the lung in its 'natural' posture, and thus optimises the ventilation-perfusion distribution, which enables lung protective ventilation and the alleviation of potentially life-threatening hypoxaemia in COVID-19 and other types of critical illness with respiratory failure. Abstract The survival benefit of proning patients with acute respiratory distress syndrome (ARDS) is well established and has recently been found to improve pulmonary gas exchange in patients with COVID-19-associated ARDS (CARDS). This review outlines the physiological implications of transitioning from supine to prone on alveolar ventilation-perfusion ( V A -- Q ) relationships during spontaneous breathing and during general anaesthesia in the healthy state, as well as during invasive mechanical ventilation in patients with ARDS and CARDS. Spontaneously breathing, awake healthy individuals maintain a small vertical (ventral-to-dorsal) V A / Q ratio gradient in the supine position, which is largely neutralised in the prone position, mainly through redistribution of perfusion. In anaesthetised and mechanically ventilated healthy individuals, a vertical V A / Q ratio gradient is present in both postures, but with better V A -- Q matching in the prone position. In ARDS and CARDS, the vertical V A / Q ratio gradient in the supine position becomes larger, with intrapulmonary shunting in gravitationally dependent lung regions due to compression atelectasis of the dorsal lung. This is counteracted by proning, mainly through a more homogeneous distribution of ventilation combined with a largely unaffected high perfusion dorsally, and a consequent substantial improvement in arterial oxygenation. The data regarding proning as a therapy in patients with CARDS is still limited and whether the associated improvement in arterial oxygenation translates to a survival benefit remains unknown. Proning is nonetheless an attractive and lung protective manoeuvre with the potential benefit of improving life-threatening hypoxaemia in patients with ARDS and CARDS.

Background Mean flow index (Mxa) for evaluating dynamic cerebral autoregulation is derived using varying approaches for calculation, which may explain that the reliability ranges from poor to excellent. The comparability, repeatability, stability, and internal consistency of approaches have not previously been assessed. Methods We included 60 recordings from resting healthy volunteers and calculated Mxa using four different approaches: three without overlapping calculations, using intervals for averaging wave‐form data (blocks) of 3, 6, and 10 s, and correlation periods (epochs) of 60, 240, and 300 s (3–60–F, 6–240–F, and 10–300–F); and one using 10‐second blocks, 300 s epochs, and overlaps of 60 s (10–300–60). The comparability between the approaches was assessed using Student's t test, intraclass correlation coefficients (ICC), and Bland–Altman plot. Results Overall, 3–60–F resulted in a higher Mxa than the other indices (p, Mx has a low sensitivity to artifacts, but otherwise seems highly dependent on the approach, with a repeatability that is moderate at best. The varying accuracy and precision renders Mx unreliable for classifying impaired cerebral autoregulation using healthy adults for comparison.

NEW FINDINGS: What is the topic of this review? Lactate is considered an important substrate for mitochondria in muscles, heart, and brain during exercise, and is the main gluconeogenetic precursor in the liver and kidneys In this light, we review the (patho)physiology of lactate metabolism in sepsis and coronavirus disease 2019 (COVID-19) What advances does it highlight? Elevated blood lactate is strongly associated with mortality in septic patients Lactate seems unrelated to tissue hypoxia, but likely reflects mitochondrial dysfunction and high adrenergic stimulation Patients with severe COVID-19 exhibit near-normal blood lactate, indicating preserved mitochondrial function, despite a systemic hyperinflammatory similar to sepsis ABSTRACT: In critically ill patients, elevated plasma lactate is often interpreted as a sign of organ hypoperfusion and/or tissue hypoxia This view on lactate is likely influenced by the pioneering exercise physiologists around 1920 August Krogh identified an oxygen deficit at the onset of exercise that was later related to an oxygen "debt" and lactate accumulation by AV Hill Lactate is considered the main gluconeogenetic precursor in the liver and kidneys during submaximal exercise, but the hepatic elimination is attenuated by splanchnic vasoconstriction at high-intensity exercise causing an exponential increase in blood lactate With the development of stable isotope tracers, lactate has become established as an important energy source for muscle, brain, and heart tissue where it is utilised for mitochondrial respiration Plasma lactate > 4 mM is strongly associated with mortality in septic shock, with no direct link between lactate release and tissue hypoxia Herein, we provide evidence for mitochondrial dysfunction and adrenergic stimulation as explanations for the sepsis-induced hyperlactatemia Despite profound hypoxaemia and intense work of breathing, patients with severe coronavirus disease 2019 (COVID-19) rarely exhibit hyperlactatemia (> 2 5 mM), while presenting a systemic hyperinflammatory state much like sepsis However, lactate dehydrogenase (LDH), which controls the formation of lactate, is markedly elevated in plasma, and strongly associated with mortality in severe COVID-19 We briefly review the potential mechanisms of the LDH elevation in COVID-19 and its relationship to lactate metabolism based on mechanisms established in contracting skeletal muscle and the acute respiratory distress syndrome This article is protected by copyright All rights reserved

Background Severe immunopathology may drive the deleterious manifestations that are observed in the advanced stages of coronavirus disease 2019 (COVID-19) but are poorly understood. Objective Our aim was to phenotype leukocyte subpopulations and the cytokine milieu in the lungs and blood of critically ill patients with COVID-19 acute respiratory distress syndrome (ARDS). Methods We consecutively included patients less than 72 hours after intubation following informed consent from their next of kin. Bronchoalveolar lavage fluid was evaluated by microscopy; bronchoalveolar lavage fluid and blood were assessed by 10-color flow cytometry and a multiplex cytokine panel. Results Four mechanically ventilated patients (aged 40-75 years) with moderate-to-severe COVID-19 ARDS were included. Immature neutrophils dominated in both blood and lungs, whereas CD4 and CD8 T-cell lymphopenia was observed in the 2 compartments. However, regulatory T cells and TH17 cells were found in higher fractions in the lung. Lung CD4 and CD8 T cells and macrophages expressed an even higher upregulation of activation markers than in blood. A wide range of cytokines were expressed at high levels both in the blood and in the lungs, most notably, IL-1RA, IL-6, IL-8, IP-10, and monocyte chemoattactant protein-1, consistent with hyperinflammation. Conclusion COVID-19 ARDS exhibits a distinct immunologic profile in the lungs, with a depleted and exhausted CD4 and CD8 T-cell population that resides within a heavily hyperinflammatory milieu., Graphical abstract

CD163 is the macrophage receptor for uptake of hemoglobin-haptoglobin complexes. The human receptor can be shed from the macrophage surface owing to a cleavage site for the inflammation-inducible TACE/ADAM17 enzyme. Accordingly, plasma ‘soluble CD163’ (sCD163) has become a biomarker for macrophage activity and inflammation. The present study disclosed that 10% of sCD163 in healthy persons is actually extracellular vesicle (EV)-associated CD163 not being cleaved and shed. Endotoxin injection of human volunteers caused a selective increase in the ectodomain CD163, while septic patients exhibited high levels of both soluble ectodomain CD163 and extracellular vesicle (EV) CD163, the latter representing up 60% of total plasma CD163. A poor prognosis of septic patients measured as the sequential organ failure assessment (SOFA) score correlated with the increase in membrane-associated CD163. Our results show that soluble ectodomain CD163 and EV CD163 in plasma are part of separate macrophage response in the context of systemic inflammation. While that soluble ectodomain CD163 is released during the acute systemic inflammatory response, this is not the case for EV CD163 that instead may be released during a later phase of the inflammatory response. A separate measurement of the two forms of CD163 constituting ‘soluble CD163’ in plasma may therefore add to the diagnostic and prognostic value.

Sepsis is frequently complicated by brain dysfunction, which may be associated with disturbances in cerebral autoregulation, rendering the brain susceptible to hypoperfusion and hyperperfusion. The purpose of the present study was to assess static and dynamic cerebral autoregulation 1) in a human experimental model of the systemic inflammatory response during early sepsis and 2) in patients with advanced sepsis. Cerebral autoregulation was tested using transcranial Doppler ultrasound in healthy volunteers ( n = 9) before and after LPS infusion and in patients with sepsis ( n = 16). Static autoregulation was tested by norepinephrine infusion and dynamic autoregulation by transfer function analysis (TFA) of spontaneous oscillations between mean arterial blood pressure and middle cerebral artery blood flow velocity in the low frequency range (0.07–0.20 Hz). Static autoregulatory performance after LPS infusion and in patients with sepsis was similar to values in healthy volunteers at baseline. In contrast, TFA showed decreased gain and an increased phase difference between blood pressure and middle cerebral artery blood flow velocity after LPS (both P < 0.01 vs. baseline); patients exhibited similar gain but lower phase difference values ( P < 0.01 vs. baseline and LPS), indicating a slower dynamic autoregulatory response. Our findings imply that static and dynamic cerebral autoregulatory performance may disassociate in sepsis; thus static autoregulation was maintained both after LPS and in patients with sepsis, whereas dynamic autoregulation was enhanced after LPS and impaired with a prolonged response time in patients. Hence, acute surges in blood pressure may adversely affect cerebral perfusion in patients with sepsis.

the ability to recognize and diagnose acid-base disorders is of the utmost importance in the clinical setting. However, in our experience, medical students often have difficulties learning the basic principles of acid-base physiology in the respiratory physiology curriculum, particularly when

Case studies from popular culture have previously been reported to be helpful teaching tools for conveying and integrating complex physiological principles.1 A most enigmatic case that has puzzled some anesthesiologists and respiratory physiologists for decades is Darth Vader, “the chosen one” from the Star Wars franchise; his continuous need for a whole-body armored suit that supports his breathing as well as his characteristic breath sounds indicate that complex pulmonary pathophysiological principles are at stake. Although the Star Wars movies apparently take place “a long time ago in a galaxy far far away” and people there have something called “midichlorions” in their cells (a fusion of mitochondria and chloroplasts?), we assumed that the respiratory physiology of Darth Vader was similar to that of Homo Sapiens on Earth, in an attempt to decipher the nature of his pulmonary disease and use him as a case for teaching pulmonary physiology and pathophysiology to medical students in our ward.

Pulmonary dysfunction is among the most frequent complications to cardiac surgeries. Exposure of blood to the cardiopulmonary bypass (CPB) circuit with subsequent lung ischemia-reperfusion leads to the production of inflammatory mediators and increases in microvascular permeability. The study aimed to elucidate histological, cellular, and metabolite changes following two lung protective regimens during CPB with Histidine-Tryptophan-Ketoglutarate (HTK) enriched or warm oxygenated blood pulmonary perfusion compared to standard regimen with no pulmonary perfusion. A total of 90 patients undergoing CPB were randomized to receiving HTK, oxygenated blood or standard regimen. Of these, bronchoalveolar lavage fluid (BALF) and lung tissue biopsies were obtained before and after CPB from 47 and 25 patients, respectively. Histopathological scores, BALF cell counts and metabolite screening were assessed. Multivariate and univariate analyses were performed. Profound histological, cellular, and metabolic changes were identified in all patients after CPB. Histological and cellular changes were similar in the three groups, however, some metabolite profiles were different in the HTK patients. While all patients presented an increase in inflammatory cells, metabolic acidosis, protease activity and oxidative stress, HTK patients seemed to be protected against severe acidosis, excessive fatty acid oxidation, and inflammation during ischemia-reperfusion. Additional studies are needed to confirm these findings.

Angiotensins different from ANG II exhibit biological activities, possibly mediated via receptors other than ANG II receptors. We studied the effects of 3-h infusions of ANG III, ANG-(1-7), and ANG IV in doses equimolar to physiological amounts of ANG II (3 pmol · kg-1 · min-1), in six men on low-sodium diet (30 mmol/day). The subjects were acutely pretreated with canrenoate and captopril to inhibit aldosterone actions and ANG II synthesis, respectively. ANG II infusion increased plasma angiotensin immunoreactivity to 53 ± 6 pg/ml (+490%), plasma aldosterone to 342 ± 38 pg/ml (+109%), and blood pressure by 27%. Glomerular filtration rate decreased by 16%. Concomitantly, clearance of endogenous lithium fell by 66%, and fractional proximal reabsorption of sodium increased from 77 to 92%; absolute proximal reabsorption rate of sodium remained constant. ANG II decreased sodium excretion by 70%, potassium excretion by 50%, and urine flow by 80%, whereas urine osmolality increased. ANG III also increased plasma aldosterone markedly (+45%), however, without measurable changes in angiotensin immunoreactivity, glomerular filtration rate, or renal excretion rates. During vehicle infusion, plasma renin activity decreased markedly (∼700 to ∼200 mIU/l); only ANG II enhanced this decrease. ANG-(1-7) and ANG IV did not change any of the measured variables persistently. It is concluded that 1) ANG III and ANG IV are cleared much faster from plasma than ANG II, 2) ANG II causes hypofiltration, urinary concentration, and sodium and potassium retention at constant plasma concentrations of vasopressin and atrial natriuretic peptide, and 3) a very small increase in the concentration of ANG III, undetectable by usual techniques, may increase aldosterone secretion substantially.

Evidence of biological activity of fragments of ANG II is accumulating. Fragments considered being inactive degradation products might mediate actions previously attributed to ANG II. The study aimed to determine whether angiotensin fragments exert biological activity when administered in amounts equimolar to physiological doses of ANG II. Cardiovascular, endocrine, and renal effects of ANG II, ANG III, ANG IV, and ANG-(1-7) (6 pmol·kg-1·min-1) were investigated in conscious dogs during acute inhibition of angiotensin I-converting enzyme (enalaprilate) and aldosterone (canrenoate). Furthermore, ANG III was investigated by step-up infusion (30 and 150 pmol·kg-1·min-1). Arterial plasma concentrations [ANG immunoreactivity (IR)] were determined by an ANG II antibody cross-reacting with ANG III and ANG IV. Metabolic clearance rates were higher for ANG III and ANG IV (391 ± 19 and 274 ± 13 ml·kg-1·min-1, respectively) than for ANG II (107 ± 13 ml·kg-1·min-1). ANG II increased ANG IR by 60 ± 7 pmol/ml, blood pressure by 30%, increased plasma aldosterone markedly (to 345 ± 72 pg/ml), and plasma vasopressin transiently, while reducing glomerular filtration rate (40 ± 2 to 33 ± 2 ml/min), sodium excretion (50 ± 7 to 16 ± 4 μmol/min), and urine flow. Equimolar amounts of ANG III induced similar antinatriuresis (57 ± 8 to 19 ± 3 μmol/min) and aldosterone secretion (to 268 ± 71 pg/ml) at much lower ANG IR increments (∼1/7) without affecting blood pressure, vasopressin, or glomerular filtration rate. The effects of ANG III exhibited complex dose-response relations. ANG IV and ANG-(1-7) were ineffective. It is concluded that 1) plasma clearances of ANG III and ANG IV are higher than those of ANG II; 2) ANG III is more potent than ANG II in eliciting immediate sodium and potassium retention, as well as aldosterone secretion, particularly at low concentrations; and 3) the complexity of the ANG III dose-response relationships provides indirect evidence that several effector mechanisms are involved.

SUMMARY We report a case of cerebral aspergilloma in a 25-yearold immunoincompetent man admitted to a general intensive care unit. Monitoring of intracranial pressure was instigated and revealed hour-long epochs of severe intracranial hypertension, despite a normal opening pressure, with decreases in cerebral perfusion pressure. We documented that this was associated with cerebral hypoperfusion by transcranial Doppler ultrasound. The present case illustrates that severe intracranial hypertension may evolve despite a normal opening pressure; it furthermore shows that continuous monitoring of intracranial pressure may be used to predict changes in cerebral haemodynamics in critically ill patients with neuroinfection.

BACKGROUND: Sepsis induces early activation of coagulation and fibrinolysis followed by late fibrinolytic shutdown and progressive endothelial damage. The aim of the present study was to investigate and compare the functional hemostatic response in whole blood and plasma during experimental human endotoxemia by the platelet function analyzer, Multiplate and by standard and modified thrombelastography (TEG).METHODS: Prospective physiologic study of nine healthy male volunteers undergoing endotoxemia by means of a 4-hour infusion of E. coli lipopolysaccharide (LPS, 0.5 ng/kg/hour), with blood sampled at baseline and at 4 h and 6 h. Physiological and standard biochemical data and coagulation tests, TEG (whole blood: TEG, heparinase-TEG, Functional Fibrinogen; plasma: TEG±tissue-type plasminogen activator (tPA)) and Multiplate (TRAPtest, ADPtest, ASPItest, COLtest) were recorded. Mixed models with Tukey post hoc tests and correlations were applied.RESULTS: Endotoxemia induced acute SIRS with increased HR, temperature, WBC, CRP and procalcitonin and decreased blood pressure. It also induced a hemostatic response with platelet consumption and reduced APTT while INR increased (all pCONCLUSIONS: Endotoxemia induced a hemostatic response with reduced primary but enhanced secondary hemostasis, enhanced early fibrinolysis and fibrinogen consumption followed by downregulation of fibrinolysis, with a discrepant fibrinolytic response in plasma and whole blood. The finding that blood cells are critically involved in the vasculo-fibrinolytic response to acute inflammation is important given that disturbances in the vascular system contribute significantly to morbidity and mortality in critically ill patients.

Quiz-based and collaborative teaching strategies have previously been found to be efficient for the improving meaningful learning of physiology during lectures. These approaches have, however, not been investigated during laboratory exercises. In the present study, we compared the impact of solving quizzes individually and in groups with conventional teaching on the immediate learning during a laboratory exercise. We implemented two quizzes in a mandatory 4-h laboratory exercise on baroreflex physiology. A total of 155 second-year medical students were randomized to solve quizzes individually ( intervention group I, n = 57), in groups of three to four students ( intervention group II, n = 56), or not to perform any quizzes (control; intervention group III, n = 42). After the laboratory exercise, all students completed an individual test, which encompassed two recall questions, two intermediate questions, and two integrated questions. The integrated questions were of moderate and advanced difficulty, respectively. Finally, students completed an evaluation form. Intervention group I reached the highest total test scores and proved best at answering the integrated question of advanced difficulty. Moreover, there was an overall difference between groups for student evaluations of the quality of the teaching, which was highest for intervention group II. In conclusion, solving quizzes individually during a laboratory exercise may enhance learning, whereas solving quizzes in groups is associated with higher student satisfaction.

Introduction Sepsis may be associated with disturbances in cerebral oxygen transport and cerebral haemodynamic function, thus rendering the brain particularly susceptible to hypoxia. The purpose of this study was to assess the impact of isocapnic hypoxia and hyperoxia on dynamic cerebral autoregulation in a human-experimental model of the systemic inflammatory response during the early stages of sepsis. Methods A total of ten healthy volunteers were exposed to acute isocapnic inspiratory hyperoxia (FIO2 = 40%) and hypoxia (FIO2 = 12%) before and after a 4-hour lipopolysaccharide (LPS) infusion (2 ng kg-1). Middle cerebral artery blood follow velocity was assessed using transcranial Doppler ultrasound, and dynamic autoregulation was evaluated by transfer function analysis. Results Transfer function analysis revealed an increase in the phase difference between mean arterial blood pressure and middle cerebral artery blood flow velocity in the low frequency range (0.07–0.20 Hz) after LPS (P