Test-retest reliability of transfer function analysis metrics for assessing dynamic cerebral autoregulation to spontaneous blood pressure oscillations.

Transfer function analysis (TFA) is a widely used method for assessing dynamic cerebral autoregulation in humans. In the present study, we assessed the test-retest reliability of established TFA metrics derived from spontaneous blood pressure oscillations and based on 5 min recordings. The TFA-based gain, phase and coherence in the low-frequency range (0.07-0.20 Hz) from 19 healthy volunteers, 37 patients with subarachnoid haemorrhage and 19 patients with sepsis were included. Reliability assessments included the smallest real difference (SRD) and the coefficient of variance for comparing consecutive 5 min recordings, temporally separated 5 min recordings and consecutive recordings with a minimal length of 10 min. In healthy volunteers, temporally separating the 5 min recordings led to a 0.38 (0.01-0.79) cm s-1 mmHg-1 higher SRD for gain (P = 0.032), and extending the duration of recordings did not affect the reliability. In subarachnoid haemorrhage, temporal separation led to a 0.85 (-0.13 to 1.93) cm s-1 mmHg-1 higher SRD (P = 0.047) and a 20 (-2 to 41)% higher coefficient of variance (P = 0.038) for gain, but neither metric was affected by extending the recording duration. In sepsis, temporal separation increased the SRD for phase by 94 (23-160)° (P = 0.006) but was unaffected by extending the recording. A recording duration of 8 min was required to achieve stable gain and normalized gain measures in healthy individuals, and even longer recordings were required in patients. In conclusion, a recording duration of 5 min appears insufficient for obtaining stable and reliable TFA metrics when based on spontaneous blood pressure oscillations, particularly in critically ill patients with subarachnoid haemorrhage and sepsis.

Pulmonary blood volume measured by 82Rb-PET in patients with chronic obstructive pulmonary disease: a retrospective cohort study.

In patients with chronic obstructive pulmonary disease (COPD), pulmonary vascular dysfunction and destruction are observable before the onset of detectable emphysema, but it is unknown whether this is associated with central hypovolemia. We investigated if COPD patients have reduced pulmonary blood volume (PBV) evaluated by 82Rb-positron emission tomography(PET) at rest and during adenosine-induced hyperemia. This single-center retrospective cohort study assessed 6301 82Rb-PET myocardial perfusion imaging (MPI) examinations performed over a 6-year period. We compared 77 COPD patients with 44 healthy kidney donors (controls). Cardiac output (Q̇) and mean 82Rb bolus transit time (MBTT) were used to calculate PBV. Q̇ was similar at rest (COPD: 3649 ± 120 mL vs. control: 3891 ± 160 mL, p=0.368) but lower in COPD patients compared to controls during adenosine infusion (COPD: 5432 ± 124 mL vs. control: 6185 ± 161 mL, p < 0.050). MBTT was shorter in COPD patients compared to controls at rest (COPD: 8.7 ± 0.28 seconds vs. control: 11.4 ± 0.37 seconds, p < 0.001) and during adenosine infusion (COPD: 9.2 ± 0.28 seconds vs. control: 10.2 ± 0.37 seconds, p < 0.014). PBV was lower in COPD patients, even after adjustment for body surface area, sex, and age at rest (COPD: 530 (29) mL vs. 708 (38) mL, p < 0.001) and during adenosine infusion (COPD: 826 (29) mL vs. 1044 (38) mL, p<0.001). In conclusion, patients with COPD show evidence of central hypovolemia, but it remains to be determined whether this has any diagnostic or prognostic impact.

Alveolar cytokines and interferon autoantibodies in COVID-19 ARDS.

Background: Type I interferon (IFN-I) and IFN autoantibodies play a crucial role in controlling SARS-CoV-2 infection. The levels of these mediators have only rarely been studied in the alveolar compartment in patients with COVID-19 acute respiratory distress syndrome (CARDS) but have not been compared across different ARDS etiologies, and the potential effect of dexamethasone (DXM) on these mediators is not known. Methods: We assessed the integrity of the alveolo-capillary membrane, interleukins, type I, II, and III IFNs, and IFN autoantibodies by studying the epithelial lining fluid (ELF) volumes, alveolar concentration of protein, and ELF-corrected concentrations of cytokines in two patient subgroups and controls. Results: A total of 16 patients with CARDS (four without and 12 with DXM treatment), eight with non-CARDS, and 15 healthy controls were included. The highest ELF volumes and protein levels were observed in CARDS. Systemic and ELF-corrected alveolar concentrations of interleukin (IL)-6 appeared to be particularly low in patients with CARDS receiving DXM, whereas alveolar levels of IL-8 were high regardless of DXM treatment. Alveolar levels of IFNs were similar between CARDS and non-CARDS patients, and IFNα and IFNω autoantibody levels were higher in patients with CARDS and non-CARDS than in healthy controls. Conclusions: Patients with CARDS exhibited greater alveolo-capillary barrier disruption with compartmentalization of IL-8, regardless of DXM treatment, whereas systemic and alveolar levels of IL-6 were lower in the DXM-treated subgroup. IFN-I autoantibodies were higher in the BALF of CARDS patients, independent of DXM, whereas IFN autoantibodies in plasma were similar to those in controls.

Characterization of differences in immune responses during bolus and continuous infusion endotoxin challenges using mathematical modelling.

Endotoxin administration is commonly used to study the inflammatory response, and though traditionally given as a bolus injection, it can be administered as a continuous infusion over multiple hours. Several studies hypothesize that the latter better represents the prolonged and pronounced inflammation observed in conditions like sepsis. Yet very few experimental studies have administered endotoxin using both strategies, leaving significant gaps in determining the underlying mechanisms responsible for their differing immune responses. We used mathematical modelling to analyse cytokine data from two studies administering a 2 ng kg-1 dose of endotoxin, one as a bolus and the other as a continuous infusion over 4 h. Using our model, we simulated the dynamics of mean and subject-specific cytokine responses as well as the response to long-term endotoxin administration. Cytokine measurements revealed that the bolus injection led to significantly higher peaks for interleukin (IL)-8, while IL-10 reaches higher peaks during continuous administration. Moreover, the peak timing of all measured cytokines occurred later with continuous infusion. We identified three model parameters that significantly differed between the two administration methods. Monocyte activation of IL-10 was greater during the continuous infusion, while tumour necrosis factor α $ {\alpha} $ and IL-8 recovery rates were faster for the bolus injection. This suggests that a continuous infusion elicits a stronger, longer-lasting systemic reaction through increased stimulation of monocyte anti-inflammatory mediator production and decreased recovery of pro-inflammatory catalysts. Furthermore, the continuous infusion model exhibited prolonged inflammation with recurrent peaks resolving within 2 days during long-term (20-32 h) endotoxin administration.

Pulmonary diffusing capacity for carbon monoxide and nitric oxide after COVID-19: A prospective cohort study (the SECURe study).

Many patients exhibit persistently reduced pulmonary diffusing capacity after coronavirus disease 2019 (COVID-19). In this study, dual test gas diffusing capacity for carbon monoxide and nitric oxide (DL,CO,NO) metrics and their relationship to disease severity and physical performance were examined in patients who previously had COVID-19. An initial cohort of 148 patients diagnosed with COVID-19 of all severities between March 2020 and March 2021 had a DL,CO,NO measurement performed using the single-breath method at 5.7 months follow-up. All patients with at least one abnormal DL,CO,NO metric (n = 87) were revaluated at 12.5 months follow-up. The DL,CO,NO was used to provide the pulmonary diffusing capacity for nitric oxide (DL,NO), the pulmonary diffusing capacity for carbon monoxide (DL,CO,5s), the alveolar-capillary membrane diffusing capacity and the pulmonary capillary blood volume. At both 5.7 and 12.5 months, physical performance was assessed using a 30 s sit-to-stand test and the 6 min walk test. Approximately 60% of patients exhibited a severity-dependent decline in at least one DL,CO,NO metric at 5.7 months follow-up. At 12.5 months, both DL,NO and DL,CO,5s had returned towards normal but still remained abnormal in two-thirds of the patients. Concurrently, improvements in physical performance were observed, but with no apparent relationship to any DL,CO,NO metric. The severity-dependent decline in DL,NO and DL,CO observed at 5.7 months after COVID-19 appears to be reduced consistently at 12.5 months follow-up in the majority of patients, despite marked improvements in physical performance.

Ventilation perfusion functional difference images in lung SPECT: A linear and symmetrical scale as an alternative to the ventilation perfusion ratio.

PURPOSE: Ventilation Perfusion SPECT is important in the diagnostics of e.g. pulmonary embolism and chronic obstructive pulmonary disease. Classical and reverse mismatched defects can be identified by utilizing the ventilation-perfusion ratio. Unfortunately, this ratio is only linear in the ventilation, the scale is not symmetrical regarding classical and reversed mismatches and small perfusion values give rise to artifacts. The ventilation-perfusion (VQ) difference is developed as an alternative. METHODS: For both VQ-ratio and VQ-difference a scaling factor for the perfusion is computed, so that voxels with matched ventilation and perfusion (on average) yield zero signal. The relative VQ-difference is calculated by scaling with the summed VQ-signal in each voxel. The scaled VQ-difference is calculated by scaling with the global maximum of this sum. RESULTS: The relative and scaled differences have a scale from -1 (perfusion only) to + 1 (ventilation only). Image quality of relative VQ-difference and VQ-ratio images is hampered by artifacts from areas with both low perfusion and low ventilation. Ratio and differences have been investigated in ten patients and are shown for three patients (one without defects). Clinical thresholds for the difference images are derived resulting in color maps of relevant (reversed) mismatches with a (reciprocal) ratio larger than two. CONCLUSIONS: The relative ventilation-perfusion difference is a methodological improvement on the ventilation-perfusion ratio, because it has a symmetrical scale and is bound on a closed domain. A better diagnostic value is expected by utilizing the scaled difference, which represents functional difference instead of relative difference.

Myths and methodologies: Assessment of dynamic cerebral autoregulation by the mean flow index.

The mean flow index-usually referred to as Mx-has been used for assessing dynamic cerebral autoregulation (dCA) for almost 30 years. However, concerns have arisen regarding methodological consistency, construct and criterion validity, and test-retest reliability. Methodological nuances, such as choice of input (cerebral perfusion pressure, invasive or non-invasive arterial pressure), pre-processing approach and artefact handling, significantly influence mean flow index values, and previous studies correlating mean flow index with other established dCA metrics are confounded by inherent methodological flaws like heteroscedasticity, while the mean flow index also fails to discriminate individuals with presumed intact versus impaired dCA (discriminatory validity), and its prognostic performance (predictive validity) across various conditions remains inconsistent. The test-retest reliability, both within and between days, is generally poor. At present, no single approach for data collection or pre-processing has proven superior for obtaining the mean flow index, and caution is advised in the further use of mean flow index-based measures for assessing dCA, as current evidence does not support their clinical application.

Severe hypoxaemic hypercapnia compounds cerebral oxidative-nitrosative stress during extreme apnoea: Implications for cerebral bioenergetic function.

We examined the extent to which apnoea-induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra-elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end-apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri-iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015-0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative-nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S-nitrosohaemoglobin consumption and plasma S-nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative-nitrosative stress. KEY POINTS: Local sampling of blood across the cerebral circulation in ultra-elite apnoeists determined the extent to which severe end-apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical-mediated nitric oxide bioavailability and global cerebral bioenergetic function. Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative-nitrosative stress. The apnoea-induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose. Cerebral oxidative-nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea-induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia. This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production.

Dual Test Gas Pulmonary Diffusing Capacity Measurement During Exercise in Humans Using the Single-Breath Method.

The combined single-breath measurement of the diffusing capacity of carbon monoxide (DL,CO) and nitric oxide (DL,NO) is a useful technique to measure pulmonary alveolar-capillary reserve in both healthy and patient populations. The measurement provides an estimate of the participant's ability to recruit and distend pulmonary capillaries. The method has recently been reported to exhibit a high test-retest reliability in healthy volunteers during exercise of light to moderate intensity. Of note, this technique permits up to 12 repeated maneuvers and only requires a single breath with a relatively short breath-hold time of 5 s. Representative data are provided showing the gradual changes in DL,NO and DL,CO from rest to exercise at increasing intensities of up to 60% of maximal workload. The measurement of diffusing capacity and evaluation of alveolar-capillary reserve is a useful tool to evaluate the lung's ability to respond to exercise both in the healthy population as well as in patient populations such as those with chronic lung disease.

Long-term non-invasive ventilation for COPD patients following an exacerbation with acute hypercapnic respiratory failure: a randomized controlled trial.

Introduction: It remains unclear whether long-term non-invasive ventilation (LT-NIV) for patients with chronic obstructive pulmonary disease (COPD) improves survival and reduces admissions as results from randomized trials are inconsistent. We aim to determine whether LT-NIV initiated after an admission with acute hypercapnic respiratory failure (AHRF) can affect survival and admission rate in COPD patients. Methods: A randomized controlled open-label trial, allocating patients with COPD to LT-NIV or standard of care immediately after an admission with AHRF treated with acute NIV. LT-NIV was aimed to normalize PaCO2 using high-pressure NIV. Results: The study was discontinued before full sample size due to slow recruitment. 28 patients were randomized to LT-NIV and 27 patients to standard of care. 42% of patients had a history of ≥ 2 admissions with AHRF. Median IPAP was 24 cmH2O (IQR 20-28). The primary outcome, time to readmission with AHRF or death within 12 months, did not reach significance, hazard ratio 0.53 (95% CI 0.25-1.12) p = 0.097. In a competing risk analysis, adjusted for history of AHRF, the odds ratio for AHRF within 12 months was 0.30 (95% CI 0.11-0.87) p = 0.024. The LT-NIV group had less exacerbations (median 1 (0-1) vs 2 (1-4) p = 0.021) and readmissions with AHRF (median 0 (0-1) vs 1 (0-1) p = 0.016). Conclusion: The risk of the primary outcome, time to readmission with AHRF or death within 12 months was numerically smaller in the LT-NIV group, however, did not reach significance. Nevertheless, several secondary outcome analyses like risk of AHRF, number of episodes of AHRF and exacerbations were all significantly reduced in favour of high-pressure LT-NIV, especially in patients with frequent AHRF.

Impact of high-intensity interval training on cardiac structure and function after COVID-19: an investigator-blinded randomized controlled trial.

A large proportion of patients suffer from a persistent reduction in cardiorespiratory fitness after recovery from COVID-19, of which the effects on the heart may potentially be reversed through the effect of high-intensity interval training (HIIT). In the present study, we hypothesized that HIIT would increase left ventricular mass (LVM) and improve functional status and health-related quality of life (HRQoL) in individuals previously hospitalized for COVID-19. In this investigator-blinded, randomized controlled trial, 12 wk of supervised HIIT (4 × 4 min, three times a week) was compared with standard care (control) in individuals recently discharged from hospital due to COVID-19. LVM was assessed by cardiac magnetic resonance imaging (cMRI, primary outcome), whereas the pulmonary diffusing capacity (DLCOc, secondary outcome) was examined by the single-breath method. Functional status and HRQoL were assessed by Post-COVID-19 functional scale (PCFS) and King's brief interstitial lung disease (KBILD) questionnaire, respectively. A total of 28 participants were included (age 57 ± 10, 9 females; HIIT: 58 ± 11, 4 females; standard care: 57 ± 9, 5 females), LVM increased in the HIIT vs. standard care group with a between-group difference of 6.8 [mean, 95%CI: 0.8; 12.8] g; P = 0.029. There were no between-group differences in DLCOc or any other lung function metric, which gradually resolved in both groups. Descriptively, PCFS suggested fewer functional limitations in the HIIT group. KBILD improved similarly in the two groups. HIIT is an efficacious exercise intervention for increasing LVM in individuals previously hospitalized for COVID-19.NEW & NOTEWORTHY In this randomized clinical trial on individuals previously hospitalized for COVID-19, a 12 wk supervised high-intensity interval training (HIIT) scheme was found to increase left ventricular mass, whereas pulmonary diffusing capacity was unaffected. The findings indicate that HIIT is an efficacious exercise intervention for targeting the heart after COVID-19.

Skeletal muscle protein turnover responses to parenteral nutrition in patients with alcoholic liver cirrhosis and sarcopenia.

Alcoholic liver cirrhosis (ALC) is accompanied by sarcopenia. The aim of this study was to investigate the acute effects of balanced parenteral nutrition (PN) on skeletal muscle protein turnover in ALC. Eight male patients with ALC and seven age- and sex-matched healthy controls were studied for 3 h of fasting followed by 3 h of intravenous PN (SmofKabiven 1,206 mL: amino acid = 38 g, carbohydrates = 85 g, and fat = 34 g) 4 mL/kg/h. We measured leg blood flow and sampled paired femoral arteriovenous concentrations and quadriceps muscle biopsies while providing a primed continuous infusion of [ring-2d5]-phenylalanine to quantify muscle protein synthesis and breakdown. Patients with ALC exhibited shorter 6-min walking distance (ALC: 487 ± 38 vs. controls: 722 ± 14 m, P < 0.05), lower hand-grip strength (ALC: 34 ± 2 vs. controls: 52 ± 2 kg, P < 0.05), and computed tomography (CT)-verified leg muscle loss (ALC: 5,922 ± 246 vs. controls: 8,110 ± 345 mm2, P < 0.05). Net leg muscle phenylalanine uptake changed from negative (muscle loss) during fasting to positive (muscle gain) in response to PN (ALC: -0.18 ± +0.01 vs. 0.24 ± 0.03 µmol/kg muscle·min-1; P < 0.001 and controls: -0.15 ± 0.01 vs. 0.09 ± 0.01 µmol/kg muscle·min-1; P < 0.001) but with higher net muscle phenylalanine uptake in ALC than controls (P < 0.001). Insulin concentrations were substantially higher in patients with ALC during PN. Our results suggest a higher net muscle phenylalanine uptake during a single infusion of PN in stable patients with ALC with sarcopenia compared with healthy controls.NEW & NOTEWORTHY Muscle protein turnover responses to parenteral nutritional (PN) supplementation have not previously been studied in stable alcoholic liver cirrhosis (ALC). We applied stable isotope tracers of amino acids to directly quantify net muscle protein turnover responses to PN in sarcopenic males with ALC and healthy controls. We found a higher net muscle protein gain in ALC during PN, thereby providing the physiological rationale for future clinical trials of PN as a potential countermeasure to sarcopenia.

Pulmonary blood volume assessment from a standard cardiac rubidium-82 imaging protocol: impact of adenosine-induced hyperemia.

BACKGROUND: This study aimed to assess the feasibility of estimating the pulmonary blood volume noninvasively using standard Rubidium-82 myocardial perfusion imaging (MPI) and characterize the changes during adenosine-induced hyperemia. METHODS: This study comprised 33 healthy volunteers (15 female, median age = 23 years), of which 25 underwent serial rest/adenosine stress Rubidium-82 MPI sessions. Mean bolus transit times (MBTT) were obtained by calculating the time delay from the Rubidium-82 bolus arrival in the pulmonary trunk to the arrival in the left myocardial atrium. Using the MBTT, in combination with stroke volume (SV) and heart rate (HR), we estimated pulmonary blood volume (PBV = (SV × HR) × MBTT). We report the empirically measured MBTT, HR, SV, and PBV, all stratified by sex [male (M) vs female (F)] as mean (SD). In addition, we report grouped repeatability measures using the within-subject repeatability coefficient. RESULTS: Mean bolus transit times was shortened during adenosine stressing with sex-specific differences [(seconds); Rest: Female (F) = 12.4 (1.5), Male (M) = 14.8 (2.8); stress: F = 8.8 (1.7), M = 11.2 (3.0), all P ≤ 0.01]. HR and SV increased during stress MPI, with a concomitant increase in the PBV [mL]; Rest: F = 544 (98), M = 926 (105); Stress: F = 914 (182), M = 1458 (338), all P < 0.001. The following test-retest repeatability measures were observed for MBTT (Rest = 17.2%, Stress = 17.9%), HR (Rest = 9.1%, Stress = 7.5%), SV (Rest = 8.9%, Stress = 5.6%), and for PBV measures (Rest = 20.7%, Stress = 19.5%) CONCLUSION: Pulmonary blood volume can be extracted by cardiac rubidium-82 MPI with excellent test-retest reliability, both at rest and during adenosine-induced hyperemia.

Effect of a 12-week high-intensity exercise intervention: a comparison of cardiac exercise adaptations during biological disease-modifying antirheumatic drug treatment (TNF inhibitors vs IL-6 signalling inhibitors) in patients with rheumatoid arthritis - study protocol for a randomised controlled trial.

INTRODUCTION: The chronic inflammatory state in rheumatoid arthritis (RA) augments the risk of cardiovascular disease (CVD), with pro-inflammatory cytokines tumour necrosis factor (TNF) and interleukin 6 (IL-6) playing a vital role. Consequently, biological disease-modifying antirheumatic drugs (bDMARDs) may attenuate that risk. IL-6 is also a myokine, secreted from exercising skeletal muscles, where IL-6 exhibits anti-inflammatory effects that may ameliorate the risk of CVD. In healthy humans treated with IL-6 signalling inhibitors (IL-6i), exercise induced loss of visceral fat mass and cardiac adaptations were abolished. We hypothesise that IL-6 signalling inhibition will impair the cardiac and metabolic adaptions to exercise training compared with TNF inhibition in RA patients. METHODS AND ANALYSIS: 80 RA patients treated with IL-6i (n=40) or TNF inhibitors (n=40) are included in a 12-week randomised investigator-blinded 4×4 min high-intensity interval training (HIIT) study. Patients are stratified for medical treatment and sex and allocated 1:1 to an exercise or a no exercise control group (four groups). The supervised exercise intervention comprises 3 weekly HIIT sessions on an ergometer bicycle. The primary outcome is the change in left ventricular mass (LVM), and key secondary outcome is change in visceral fat mass. Both outcomes are measured by MRI. Primary statistical analysis will evaluate LVM at follow-up in a regression model. Intention-to-treat and per protocol analyses will be conducted. The latter necessitates a minimum attendance rate of 80%, adherence to bDMARDs treatment of ≥80% and minimum 8 min (50%) of maximal heart rate above 85% per session. ETHICS AND DISSEMINATION: The study has been approved by the Capital Region Ethics Committee (H-21010559 amendments 86424, 87463 and 88044) and the Danish Medicines Agency (2021-b005287-21). The trial will follow ICH-GCP guidelines. Regardless of outcome, results will be published in relevant peer-reviewed journals. TRIAL REGISTRATION NUMBERS: Eudra-CT: 2021-b005287-21 and NCT05215509.

Heterogeneous Treatment Effects after Inspiratory Muscle Training during Recovery from Postacute COVID-19 Syndrome.

PURPOSE: The objective of this study is to investigate whether heterogeneous treatment effects occur for changes in inspiratory muscle strength, perceived dyspnea, and health-related quality of life after 8 wk of unsupervised home-based inspiratory muscle training (IMT) in adults with postacute coronavirus disease 2019 (COVID-19) syndrome. METHODS: In total, 147 adults with self-reported prior COVID-19 either completed an 8-wk home-based IMT intervention ( n = 111, 92 females, 48 ± 11 yr, 9.3 ± 3.6 months postacute COVID-19 infection) or acted as "usual care" wait list controls ( n = 36, 34 females, 49 ± 12 yr, 9.4 ± 3.2 months postacute COVID-19 infection). RESULTS: Applying a Bayesian framework, we found clear evidence of heterogeneity of treatment response for inspiratory muscle strength: the estimated difference between standard deviations (SD) of the IMT and control groups was 22.8 cm H 2 O (75% credible interval (CrI), 4.7-37.7) for changes in maximal inspiratory pressure (MIP) and 86.8 pressure time units (75% CrI, 55.7-116.7) for sustained MIP (SMIP). Conversely, there were minimal differences in the SD between the IMT and the control group for changes in perceived dyspnea and health-related quality of life, providing no evidence of heterogeneous treatment effects. Higher cumulative power during the IMT intervention was related to changes in MIP ( ß = 10.9 cm H 2 O (95% CrI, 5.3-16.8) per 1 SD) and SMIP ( ß = 63.7 (32.2-95.3) pressure time units per 1 SD), clearly indicating an IMT dose response for changes in inspiratory muscle strength. Older age (>50 yr), a longer time postacute COVID-19 (>3 months), and greater severity of dyspnea at baseline were also associated with smaller improvements in inspiratory muscle strength. CONCLUSIONS: Heterogeneous individual responses occurred after an 8-wk home-based IMT program in people with postacute COVID-19 syndrome. Consistent with standard exercise theory, larger improvements in inspiratory muscle strength are strongly related to a greater cumulative dose of IMT.

Effect of controlled blood pressure increase on cerebral blood flow velocity and oxygenation in patients with subarachnoid haemorrhage.

BACKGROUND: Patients with aneurysmal subarachnoid haemorrhage (SAH) might have impaired cerebral autoregulation, that is, CBF - and thereby oxygen delivery - passively increase with an increase in CPP. This physiological study aimed to investigate the cerebral haemodynamic effects of controlled blood pressure increase in the early phase after SAH before any signs of delayed cerebral ischaemia (DCI) occurred. METHODS: The study was carried out within 5 days after ictus. Data were recorded at baseline and after 20 min of noradrenaline infusion to increase mean arterial blood pressure (MAP) by a maximum of 30 mmHg and to an absolute level of no more than 130 mmHg. The primary outcome was the difference in middle cerebral artery blood flow velocity (MCAv) measured by transcranial Doppler (TCD), while differences in intracranial pressure (ICP), brain tissue oxygen tension (PbtO2 ), and microdialysis markers of cerebral oxidative metabolism and cell injury were assessed as exploratory outcomes. Data were analysed using Wilcoxon signed-rank test with correction for multiplicity for the exploratory outcomes using the Benjamini-Hochberg correction. RESULTS: Thirty-six participants underwent the intervention 4 (median, IQR: 3-4.75) days after ictus. MAP was increased from 82 (IQR: 76-85) to 95 (IQR: 88-98) mmHg (p-value: <.001). MCAv remained stable (baseline, median 57, IQR: 46-70 cm/s; controlled blood pressure increase, median: 55, IQR: 48-71 cm/s; p-value: .054), whereas PbtO2 increased significantly (baseline, median: 24, 95%CI: 19-31 mmHg; controlled blood pressure increase, median: 27, 95%CI: 24-33 mmHg; p-value <.001). The remaining exploratory outcomes were unchanged. CONCLUSION: In this study of patients with SAH, MCAv was not significantly affected by a brief course of controlled blood pressure increase; despite this, PbtO2 increased. This suggests that autoregulation might not be impaired in these patients or other mechanisms could mediate the increase in brain oxygenation. Alternatively, a CBF increase did occur that, in turn, increased cerebral oxygenation, but was not detected by TCD. TRIAL REGISTRATION: clinicaltrials.gov (NCT03987139; 14 June 2019).

Autonomic response to early head-up tilt in patients with severe traumatic brain injury: Analysis from a randomized feasibility trial.

Patients with severe traumatic brain injury (TBI) may have autonomic dysfunction, one manifestation of which is orthostatic intolerance. This potentially impairs physical rehabilitation. However, the exact mechanisms remain elusive. In 30 patients participating in a trial of early tilt training versus standard care and 15 healthy volunteers, 5-min electrocardiography was recorded in the supine position and during 70° head-up tilt. Heart rate variability was analyzed by the low- and high-frequency (LF and HF) power, the LF-HF ratio, the total power, the ratio of the standard deviation of normal-to-normal intervals (SDNN), the root mean square of successive differences (RMSSD), the detrended fluctuations, and sample entropy. In patients in the upright compared to the supine position, SDNN (p < 0.001), RMSSD (p < 0.001), and total power (p = 0.004) all decreased, while the remaining variables were unchanged; no long-term differences in heart rate variability in the supine position were found between early tilt training and standard care. In the healthy volunteers, all measures besides SDNN and total power changed significantly between supine and upright position. In patients with severe TBI compared to healthy volunteers, several measures of heart rate variability changed differentially during mobilization from the supine to the upright position.

Assessing cardiorespiratory fitness relative to sex improves surgical risk stratification.

BACKGROUND: To what extent sex-related differences in cardiorespiratory fitness (CRF) impact postoperative patient mortality and corresponding implications for surgical risk stratification remains to be established. METHODS: To examine this, we recruited 640 patients (366 males vs. 274 females) who underwent cardiopulmonary exercise testing prior to elective colorectal surgery. Patients were defined high risk if peak oxygen uptake was <14.3 mL kg-1  min-1 and ventilatory equivalent for carbon dioxide at 'anaerobic threshold' >34. Between-sex CRF and mortality was assessed, and sex-specific CRF thresholds predictive of mortality was calculated. RESULTS: Seventeen percent of deaths were attributed to sub-threshold CRF, which was higher than established risk factors for cardiovascular disease (CVD). The group (independent of sex) exhibited a 5-fold higher mortality (high vs. low risk patients hazard ratio = 4.80, 95% confidence interval 2.73-8.45, p < 0.001). Females exhibited 39% lower CRF (p < 0.001) with more classified high risk than males (36 vs. 23%, p = 0.001), yet mortality was not different (p = 0.544). Upon reformulation of sex-specific CRF thresholds, lower cut-offs for mortality were observed in females, and consequently, fewer (20%) were stratified with sub-threshold CRF compared to the original 36% (p < 0.001). CONCLUSIONS: Low CRF accounted for more deaths than traditional CVD risk factors, and when CRF was considered relative to sex, the disproportionate number of females stratified unfit was corrected. These findings support clinical consideration of 'sex-specific' CRF thresholds to better inform postoperative mortality and improve surgical risk stratification.