Plasma endostatin correlates with hypoxia and mortality in COVID-19-associated acute respiratory failure

Background: The contribution of endothelial injury in the pathogenesis of COVID-19-associated acute respiratory distress syndrome (ARDS) and resulting respiratory failure remains unclear. Plasma endostatin, an endogenous inhibitor of angiogenesis and endothelial dysfunction is upregulated during hypoxia, inflammation and progress of pulmonary disease. Aim: To investigate if plasma endostatin is associated to hypoxia, inflammation and 30-day mortality in patients with severe COVID-19 infection. Method: Samples for blood analysis and plasma endostatin quantification were collected from adult patients with ongoing COVID-19 (n = 109) on admission to intensive care unit (day 1). Demographic characteristics and 30-day mortality data were extracted from medical records. The ability of endostatin to predict mortality was analyzed using receiving operating characteristics and Kaplan–Meier analysis with a cutoff at 46.2 ng/ml was used to analyze the association to survival. Results: Plasma endostatin levels correlated with; PaO2/FiO2 (r = -0.3, p < 0.001), arterial oxygen tension (r = -0.2, p = 0.01), lactate (r = 0.2, p = 0.04), C-reactive protein (r = 0.2, p = 0.04), ferritin (r = 0.2, p = 0.09), D-dimer (r = 0.2, p = 0.08) and IL-6 (r = 0.4, p < 0.001). Nonsurvivors at 30 days had higher plasma endostatin levels than survivors (72 ± 26 vs 56 ± 16 ng/ml, p = 0.01). Receiving operating characteristic curve (area under the curve 0.7) showed that plasma endostatin >46.2 ng/ml predicts mortality with a sensitivity of 92% and specificity of 71%. In patients with plasma endostatin >46.2 ng/ml probability of survival was lower (p = 0.02) in comparison to those with endostatin <46.2 ng/ml. Conclusion: Our results suggest that plasma endostatin is an early biomarker for disease severity in COVID-19.

Persistent Endothelial Dysfunction in Post-Acute COVID-19 Syndrome: A Case-Control Study

Background: Endothelial dysfunction has a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its disabling complications. We designed a case-control study to assess the alterations of endothelium-dependent flow-mediated dilation (FMD) among convalescent COVID-19 patients. Methods: COVID-19 patients referred to a Pulmonary Rehabilitation Unit within 2 months from swab test negativization were consecutively evaluated for inclusion and compared to controls matched for age, gender, and cardiovascular risk factors. Results: A total of 133 convalescent COVID-19 patients (81.2% males, mean age 61.6 years) and 133 matched controls (80.5% males, mean age 60.4 years) were included. A significantly lower FMD was documented in convalescent COVID-19 patients as compared to controls (3.2% ± 2.6 vs. 6.4% ± 4.1 p < 0.001), confirmed when stratifying the study population according to age and major clinical variables. Among cases, females exhibited significantly higher FMD values as compared to males (6.1% ± 2.9 vs. 2.5% ± 1.9, p < 0.001). Thus, no significant difference was observed between cases and controls in the subgroup analysis on females (6.1% ± 2.9 vs. 5.3% ± 3.4, p = 0.362). Among convalescent COVID-19 patients, FMD showed a direct correlation with arterial oxygen tension (rho = 0.247, p = 0.004), forced expiratory volume in 1 s (rho = 0.436, p < 0.001), forced vital capacity (rho = 0.406, p < 0.001), and diffusing capacity for carbon monoxide (rho = 0.280, p = 0.008). Overall, after adjusting for major confounders, a recent COVID-19 was a major and independent predictor of FMD values (β = −0.427, p < 0.001). Conclusions: Post-acute COVID-19 syndrome is associated with a persistent and sex-biased endothelial dysfunction, directly correlated with the severity of pulmonary impairment.

Evaluation of the Effect of the Inspired Oxygen Fraction on Blood Oxygenation during Inhalant Anaesthesia in Horses: A Systematic Review with Meta-Analysis

In anaesthetized horses, pronounced ventilation/perfusion mismatching often occurs. Several authors have investigated the effect of lower inspired oxygen fractions (FiO2) to reduce formation of absorption atelectasis. This systematic review compared the effects of low (<0.6) and high (>0.8) FiO2 on the arterial oxygen tension (PaO2), the alveolar-to-arterial oxygen tension difference (P(A-a)O2), and the PaO2/FiO2 ratio in horses during inhalation anaesthesia. Using the Systematic Review Protocol for Animal Intervention Studies, four experimental and one clinical investigations were deemed suitable for inclusion. A meta-analysis was performed on the four experimental studies. The PaO2 was significantly lower (p = 0.0007, mean difference −23.54 kPa, 95% CI −37.18, −9.90) with a lower FiO2. However, the P(A-a)O2 was also significantly lower (p < 0.00001, mean difference −20.80 kPa, 95% CI −26.28, −15.32) when using a low FiO2. For the PaO2/FiO2 ratio, only one study fitted the inclusion criteria, so no meta-analysis was performed. It is concluded that, while only a limited number of studies are available, the use of a higher FiO2 in horses during inhalation anaesthesia will result in higher levels of PaO2, but also a larger P(A-a)O2 difference. Further studies are needed to increase the level of evidence on this subject.

Effect of a day-trip to altitude (2500 m) on exercise performance in pulmonary hypertension: randomised crossover trial

Question addressed by the studyTo investigate exercise performance and hypoxia-related health effects in patients with pulmonary hypertension (PH) during a high-altitude sojourn.Patients and methodsIn a randomised crossover trial in stable (same therapy for >4 weeks) patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) with resting arterial oxygen tension (PaO2) ≥7.3 kPa, we compared symptom-limited constant work-rate exercise test (CWRET) cycling time during a day-trip to 2500 m versus 470 m. Further outcomes were symptoms, oxygenation and echocardiography. For safety, patients with sustained hypoxaemia at altitude (peripheral oxygen saturation <80% for >30 min or <75% for >15 min) received oxygen therapy.Results28 PAH/CTEPH patients (n=15/n=13); 13 females; mean±sd age 63±15 years were included. After >3 h at 2500 m versus 470 m, CWRET-time was reduced to 17±11 versus 24±9 min (mean difference −6, 95% CI −10 to −3), corresponding to −27.6% (−41.1 to −14.1; p<0.001), but similar Borg dyspnoea scale. At altitude, PaO2 was significantly lower (7.3±0.8 versus 10.4±1.5 kPa; mean difference −3.2 kPa, 95% CI −3.6 to −2.8 kPa), whereas heart rate and tricuspid regurgitation pressure gradient (TRPG) were higher (86±18 versus 71±16 beats·min−1, mean difference 15 beats·min−1, 95% CI 7 to 23 beats·min−1) and 56±25 versus 40±15 mmHg (mean difference 17 mmHg, 95% CI 9 to 24 mmHg), respectively, and remained so until end-exercise (all p<0.001). The TRPG/cardiac output slope during exercise was similar at both altitudes. Overall, three (11%) out of 28 patients received oxygen at 2500 m due to hypoxaemia.ConclusionThis randomised crossover study showed that the majority of PH patients tolerate a day-trip to 2500 m well. At high versus low altitude, the mean exercise time was reduced, albeit with a high interindividual variability, and pulmonary artery pressure at rest and during exercise increased, but pressure–flow slope and dyspnoea were unchanged.

Comparison of pulmonary function in isoflurane anaesthetized ventilated sheep (Ovis aries) following administration of intravenous xylazine versus medetomidine

Alpha2 receptor agonists (alpha2-agonists) are useful sedative and analgesic agents in sheep, but have adverse pulmonary effects, which are reportedly similar between different alpha2-agonists. This randomized crossover study compared pulmonary function after intravenous administration of an alpha2-agonist, either xylazine or an equipotent dose of medetomidine in 34 female sheep anaesthetized twice. Pulmonary function was assessed using spirometry, volumetric capnography, arterial blood gas analysis 1 min prior to, and 5 and 10 min after administration of the allocated alpha 2 agonist drug. Pulmonary structural changes were subsequently assessed using computed tomography (CT). Tachypnoea or hypoxaemia prompted reversal with atipamezole and exclusion of data. Data were analysed for a fixed effect of drug using a mixed effect linear model with significance set at p < 0.05. Ten sheep administered xylazine required atipamezole while none of sheep receiving medetomidine did. Xylazine produced significantly higher respiratory frequency, airway pressures, airway resistance and arterial carbon dioxide (CO2), and lower dynamic compliance, tidal volume, CO2 elimination and end tidal CO2 tension and arterial oxygen tension than medetomidine. This was associated with a significantly lower % of aerated tissue and higher % poorly and non-aerated tissue in CT images of sheep receiving xylazine versus medetomidine. In conclusion, xylazine administration produced marked decreases in pulmonary function, in ventilated isoflurane anaesthetized sheep, when compared to an equipotent dose of medetomidine when administered as an intravenous bolus supporting the use of medetomidine when alpha2-agonists are required.

Biomarkers of Oxidative Stress for Neonatal Lung Disease

The transition from prenatal to postnatal life causes a significant increase in arterial oxygen tension and the activation of metabolic pathways enabling the newborn's adaptation to the extra-uterine environment. The balance between pro-oxidant and anti-oxidant systems is critical to preserve cellular functions. Indeed, oxidative stress (OS) occurs when the production of free radicals is not balanced by the activity of intracellular antioxidant systems, contributing to cellular and tissue damage. Perinatal OS may have serious health consequences during the postnatal period and later in life. Namely, OS has been recognized as the major cause of lung injury in newborns, especially those preterm born, due to their immature lung and antioxidant systems. The development of OS biomarkers has gained increasing research interest since they may provide useful insights about pathophysiological pathways underlying OS-mediated pulmonary diseases in newborns. Moreover, their implementation in clinical settings may help to early identify high risk-newborns and to provide targeted treatment. Ideally, a biomarker should demonstrate ease of use, biological validity and reproducibility, high sensitivity and specificity. However, none of the clinically validated biomarkers so far have been qualified for neonatal lung disease. Additionally, the complex technical procedures and the high cost of such determinations have hampered the use of OS biomarkers in clinical practice. This review aims to evaluate the current evidence on the application of biomarkers of oxidative stress for neonatal lung disease and exploring the most relevant issues affecting their implementation in practice, as well as the associated evidence gaps and research limitations.

Measuring Peripheral Chemoreflex Hypersensitivity in Heart Failure

Heart failure with reduced ejection fraction (HFrEF) induces chronic sympathetic activation. This disturbance is a consequence of both compensatory reflex disinhibition in response to lower cardiac output and patient-specific activation of one or more excitatory stimuli. The result is the net adrenergic output that exceeds homeostatic need, which compromises cardiac, renal, and vascular function and foreshortens lifespan. One such sympatho-excitatory mechanism, evident in ~40–45% of those with HFrEF, is the augmentation of carotid (peripheral) chemoreflex ventilatory and sympathetic responsiveness to reductions in arterial oxygen tension and acidosis. Recognition of the contribution of increased chemoreflex gain to the pathophysiology of HFrEF and to patients’ prognosis has focused attention on targeting the carotid body to attenuate sympathetic drive, alleviate heart failure symptoms, and prolong life. The current challenge is to identify those patients most likely to benefit from such interventions. Two assumptions underlying contemporary test protocols are that the ventilatory response to acute hypoxic exposure quantifies accurately peripheral chemoreflex sensitivity and that the unmeasured sympathetic response mirrors the determined ventilatory response. This Perspective questions both assumptions, illustrates the limitations of conventional transient hypoxic tests for assessing peripheral chemoreflex sensitivity and demonstrates how a modified rebreathing test capable of comprehensively quantifying both the ventilatory and sympathoneural efferent responses to peripheral chemoreflex perturbation, including their sensitivities and recruitment thresholds, can better identify individuals most likely to benefit from carotid body intervention.

Deep hypothermic circulatory arrest in cyanotic piglets is associated with increased neuronal necrosis

Background: The contribution of neonatal cyanosis, inherent to cyanotic congenital heart disease, to the magnitude of neurologic injury during deep hypothermic circulatory arrest has not been fully delineated. This study investigates the impact of cyanosis and deep hypothermic circulatory arrest on brain injury. Methods: Neonatal piglets were randomised to placement of a pulmonary artery to left atrium shunt to create cyanosis or sham thoracotomy. At day 7, animals were randomised to undergo deep hypothermic circulatory arrest or sham. Arterial oxygen tension and haematocrit were obtained. Neurobehavioural performance was serially assessed. The animals were sacrificed on day 14. Brain tissue was assessed for neuronal necrosis using a 5-point histopathologic score. Results: Four experimental groups were analysed (sham, n = 10; sham + deep hypothermic circulatory arrest, n = 8; shunt, n = 9; shunt + deep hypothermic circulatory arrest, n = 7). Cyanotic piglets had significantly higher haematocrit and lower partial pressure of oxygen at day 14 than non-cyanotic piglets. There were no statistically significant differences in neurobehavioural scores at day 1. However, shunt + deep hypothermic circulatory arrest piglets had evidence of greater neuronal injury than sham animals (median (range): 2 (0–4) versus 0 (0–0), p = 0.02). Discussion: Cyanotic piglets undergoing deep hypothermic circulatory arrest had increased neuronal injury compared to sham animals. Significant injury was not seen for either cyanosis or deep hypothermic circulatory arrest alone relative to shams. These findings suggest an interaction between cyanosis and deep hypothermic circulatory arrest and may partially explain the suboptimal neurologic outcomes seen in children with cyanotic heart disease who undergo deep hypothermic circulatory arrest.

EFFECTS OF STRUCTURED MANUAL HYPERINFLATION FOR IMPROVING RESPIRATORY PARAMETRS IN POST-OPERATIVE CORONARY ARTERY BYPASS GRAFT PATIENTS

Purpose: Cardiopulmonary physiotherapy plays a crucial role in cardiac rehabilitation after surgeries. The deterioration of respiratory parameters occurs after coronary artery bypass grafting (CABG) procedure. Manual hyperinflation (MHI) is done according to clinical experiences and there are no specific guidelines for it. The objectives were to determine the effects of structured manual hyperinflation for improving respiratory parameters in post-operative CABG patients. Methodology: Duration of study was 6 months (January 2019-June 2019) with a sample size of 76 post-operative CABG patients. Non-probability purposive sampling technique was used. Patients were divided into two groups’ i-e MHI and VHI depending upon the treatment protocol. In protocol, endotracheal tube (ETT) suctioning was done followed by MHI and VHI in assigned group in randomized controlled trial design. Respiratory parameters were measured by ABG’S, equations for static lung compliance and alveolar-arterial oxygen tension difference. Data was recorded pre and post ETT suctioning, immediately, 30 min and 60 min post intervention. Both males and females were included. Inclusion criteria involves patient must be intubated, hemodynamically and vitally stable, and age range 55-77 years. Those were excluded who have past medical history of diagnosed pulmonary pathology and any post-operative complications. Patient was withdrawn from the study if any subject who have unstable cardiovascular status and high levels of respiratory support. Data was analyzed on SPSS 21. Findings: All the respiratory parameters showed significant differences (p<0.05) in pre and post values of structured MHI. Significant difference (p<0.05) was observed immediately after intervention in terms of acidity (pH), partial pressure of carbon oxide (PaCO2), partial pressure of oxygen (PaO2), oxygen saturation and arterial oxygen to fraction of inspired oxygen ratio between the groups with scores higher for experimental group. HCO3 showed significant difference (p<0.05) immediately after intervention and 30 min and 60 min post intervention with the scores higher for control group. Static lung compliance showed significant difference (p<0.05) at 30 min and 60 min post intervention with scores higher for control group. Alveolar-arterial oxygen tension showed no significant difference (p>0.05) between the groups at any point. No significant difference (p>0.05) was observed between the groups at any other point of measurement for all respiratory parameters. MHI and VHI are both effective in improving respiratory parameters in post-operative CABG patients but the values were more significant in MHI group. But the difference between the groups was not significant and conclusive. Recommendations: This study should be conducted in different patient populations having different pulmonary conditions and other types of cardiac surgeries and in other patients who are intubated and mechanically ventilated. Moreover, the effects of both techniques on different variables must be studied after multiple numbers of sessions during the whole period of intubation.