A novel definition and treatment of hyperinflammation in COVID-19 based on purinergic signalling.

Hyperinflammation plays an important role in severe and critical COVID-19. Using inconsistent criteria, many researchers define hyperinflammation as a form of very severe inflammation with cytokine storm. Therefore, COVID-19 patients are treated with anti-inflammatory drugs. These drugs appear to be less efficacious than expected and are sometimes accompanied by serious adverse effects. SARS-CoV-2 promotes cellular ATP release. Increased levels of extracellular ATP activate the purinergic receptors of the immune cells initiating the physiologic pro-inflammatory immune response. Persisting viral infection drives the ATP release even further leading to the activation of the P2X7 purinergic receptors (P2X7Rs) and a severe yet physiologic inflammation. Disease progression promotes prolonged vigorous activation of the P2X7R causing cell death and uncontrolled ATP release leading to cytokine storm and desensitisation of all other purinergic receptors of the immune cells. This results in immune paralysis with co-infections or secondary infections. We refer to this pathologic condition as hyperinflammation. The readily available and affordable P2X7R antagonist lidocaine can abrogate hyperinflammation and restore the normal immune function. The issue is that the half-maximal effective concentration for P2X7R inhibition of lidocaine is much higher than the maximal tolerable plasma concentration where adverse effects start to develop. To overcome this, we selectively inhibit the P2X7Rs of the immune cells of the lymphatic system inducing clonal expansion of Tregs in local lymph nodes. Subsequently, these Tregs migrate throughout the body exerting anti-inflammatory activities suppressing systemic and (distant) local hyperinflammation. We illustrate this with six critically ill COVID-19 patients treated with lidocaine.

A feasibility study into adenosine triphosphate measurement in exhaled breath condensate: a potential bedside method to monitor alveolar deformation.

Recent research suggested an important role for pulmonary extracellular adenosine triphosphate (ATP) in the development of ventilation-induced lung injury. This injury is induced by mechanical deformation of alveolar epithelial cells, which in turn release ATP to the extracellular space. Measuring extracellular ATP in exhaled breath condensate (EBC) may be a non-invasive biomarker for alveolar deformation. Here, we study the feasibility of bedside ATP measurement in EBC. We measured ATP levels in EBC in ten subjects before and after an exercise test, which increases respiratory parameters and alveolar deformation. EBC lactate concentrations were measured as a dilution marker. We found a significant increase in ATP levels in EBC (before 73 RLU [IQR 50-209] versus after 112 RLU [IQR 86-203]; p value 0.047), and the EBC ATP-to-EBC lactate ratio increased as well (p value 0.037). We present evidence that bedside measurement of ATP in EBC is feasible and that ATP levels in EBC increase after exercise. Future research should measure ATP levels in EBC during mechanical ventilation as a potential biomarker for alveolar deformation.

Excessive Extracellular ATP Desensitizes P2Y2 and P2X4 ATP Receptors Provoking Surfactant Impairment Ending in Ventilation-Induced Lung Injury.

Stretching the alveolar epithelial type I (AT I) cells controls the intercellular signaling for the exocytosis of surfactant by the AT II cells through the extracellular release of adenosine triphosphate (ATP) (purinergic signaling). Extracellular ATP is cleared by extracellular ATPases, maintaining its homeostasis and enabling the lung to adapt the exocytosis of surfactant to the demand. Vigorous deformation of the AT I cells by high mechanical power ventilation causes a massive release of extracellular ATP beyond the clearance capacity of the extracellular ATPases. When extracellular ATP reaches levels >100 μM, the ATP receptors of the AT II cells become desensitized and surfactant impairment is initiated. The resulting alteration in viscoelastic properties and in alveolar opening and collapse time-constants leads to alveolar collapse and the redistribution of inspired air from the alveoli to the alveolar ducts, which become pathologically dilated. The collapsed alveoli connected to these dilated alveolar ducts are subject to a massive strain, exacerbating the ATP release. After reaching concentrations >300 μM extracellular ATP acts as a danger-associated molecular pattern, causing capillary leakage, alveolar space edema, and further deactivation of surfactant by serum proteins. Decreasing the tidal volume to 6 mL/kg or less at this stage cannot prevent further lung injury.

Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury.

Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-ß, α-SMA, etc.) followed by the establishment of lung fibrosis.

Time course and risk factors for myocardial dysfunction after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Myocardial wall motion abnormalities (WMAs) are independent risk factors for a poor outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). OBJECTIVE: To study the time course of WMAs during the initial phase after aSAH and to investigate which clinical, electrocardiographic, or myocardial serum markers are predictors of early or late development of WMAs. METHODS: In a prospective, multicenter cohort study in patients with aSAH, we performed serial electrocardiography and echocardiography and measured troponin T and N-terminal pro-B-type natriuretic peptide. WMAs present on admission were considered early WMAs; those that developed during the clinical course were considered late WMAs. Using multivariable regression analysis, we calculated odds ratios with corresponding 95% confidence intervals for clinical parameters, electrocardiography, and myocardial serum makers with early or late occurrence of WMAs. RESULTS: We included 301 patients (mean age ± SD, 57 ± 13) years. Multivariable odds ratios for early WMAs were poor clinical condition, 2.7 (95% confidence interval: 1.1-6.8); sinus tachycardia, 5.0 (1.3-19.9); ST-segment depression, 3.7 (1.02-13.1); ST-segment elevation, 16.6 (1.5-178.9); and increased troponin T, 2.8 (1.1-7.3). Multivariable odds ratios (95% confidence intervals) for late development of WMAs were 6.8 (1.6-30) for a myocardial infarct pattern on admission electrocardiography and 3.4 (1.4-8.5) for increased troponin T on admission. CONCLUSION: WMAs may be present on admission or develop during the course of aSAH. Poor neurological condition on admission, sinus tachycardia, ST-segment depression, and ST-segment elevation on admission electrocardiography and increased troponin T are independent predictors of early WMAs; a myocardial infarct pattern on admission ECG and increased troponin T independently predict late WMAs. CLINICAL TRIAL REGISTRATION: NCT00123695.

Detection of 'best' positive end-expiratory pressure derived from electrical impedance tomography parameters during a decremental positive end-expiratory pressure trial.

INTRODUCTION: This study compares different parameters derived from electrical impedance tomography (EIT) data to define 'best' positive end-expiratory pressure (PEEP) during a decremental PEEP trial in mechanically-ventilated patients. 'Best' PEEP is regarded as minimal lung collapse and overdistention in order to prevent ventilator-induced lung injury. METHODS: A decremental PEEP trial (from 15 to 0 cm H2O PEEP in 4 steps) was performed in 12 post-cardiac surgery patients on the ICU. At each PEEP step, EIT measurements were performed and from this data the following were calculated: tidal impedance variation (TIV), regional compliance, ventilation surface area (VSA), center of ventilation (COV), regional ventilation delay (RVD index), global inhomogeneity (GI index), and intratidal gas distribution. From the latter parameter we developed the ITV index as a new homogeneity parameter. The EIT parameters were compared with dynamic compliance and the PaO2/FiO2 ratio. RESULTS: Dynamic compliance and the PaO2/FiO2 ratio had the highest value at 10 and 15 cm H2O PEEP, respectively. TIV, regional compliance and VSA had a maximum value at 5 cm H2O PEEP for the non-dependent lung region and a maximal value at 15 cm H2O PEEP for the dependent lung region. GI index showed the lowest value at 10 cm H2O PEEP, whereas for COV and the RVD index this was at 15 cm H2O PEEP. The intratidal gas distribution showed an equal contribution of both lung regions at a specific PEEP level in each patient. CONCLUSION: In post-cardiac surgery patients, the ITV index was comparable with dynamic compliance to indicate 'best' PEEP. The ITV index can visualize the PEEP level at which ventilation of the non-dependent region is diminished, indicating overdistention. Additional studies should test whether application of this specific PEEP level leads to better outcome and also confirm these results in patients with acute respiratory distress syndrome.

Cardiac dysfunction after aneurysmal subarachnoid hemorrhage: relationship with outcome.

OBJECTIVE: To assess whether cardiac abnormalities after aneurysmal subarachnoid hemorrhage (aSAH) are associated with delayed cerebral ischemia (DCI) and clinical outcome, independent from known clinical risk factors for these outcomes. METHODS: In a prospective, multicenter cohort study, we performed echocardiography and ECG and measured biochemical markers for myocardial damage in patients with aSAH. Outcomes were DCI, death, and poor clinical outcome (death or dependency for activities of daily living) at 3 months. With multivariable Poisson regression analysis, we calculated risk ratios (RRs) with corresponding 95% confidence intervals. We used survival analysis to assess cumulative percentage of death in patients with and without echocardiographic wall motion abnormalities (WMAs). RESULTS: We included 301 patients with a mean age of 57 years; 70% were women. A wall motion score index ≥1.2 had an adjusted RR of 1.2 (0.9-1.6) for DCI, 1.9 (1.1-3.3) for death, and 1.8 (1.1-3.0) for poor outcome. Midventricular WMAs had adjusted RRs of 1.1 (0.8-1.4) for DCI, 2.3 (1.4-3.8) for death, and 2.2 (1.4-3.5) for poor outcome. For apical WMAs, adjusted RRs were 1.3 (1.1-1.7) for DCI, 1.5 (0.8-2.7) for death, and 1.4 (0.8-2.5) for poor outcome. Elevated troponin T levels, ST-segment changes, and low voltage on the admission ECGs had a univariable association with death but were not independent predictors for outcome. CONCLUSION: WMAs are independent risk factors for clinical outcome after aSAH. This relation is partly explained by a higher risk of DCI. Further study should aim at treatment strategies for these aSAH-related cardiac abnormalities to improve clinical outcome.

Ventilation distribution measured with EIT at varying levels of pressure support and Neurally Adjusted Ventilatory Assist in patients with ALI.

PURPOSE: The purpose of this study was to compare the effect of varying levels of assist during pressure support (PSV) and Neurally Adjusted Ventilatory Assist (NAVA) on the aeration of the dependent and non-dependent lung regions by means of Electrical Impedance Tomography (EIT). METHODS: We studied ten mechanically ventilated patients with Acute Lung Injury (ALI). Positive-End Expiratory Pressure (PEEP) and PSV levels were both 10 cm H2O during the initial PSV step. Thereafter, we changed the inspiratory pressure to 15 and 5 cm H2O during PSV. The electrical activity of the diaphragm (EAdi) during pressure support ten was used to define the initial NAVA gain (100 %). Thereafter, we changed NAVA gain to 150 and 50 %, respectively. After each step the assist level was switched back to PSV 10 cm H2O or NAVA 100 % to get a new baseline. The EIT registration was performed continuously. RESULTS: Tidal impedance variation significantly decreased during descending PSV levels within patients, whereas not during NAVA. The dorsal-to-ventral impedance distribution, expressed according to the center of gravity index, was lower during PSV compared to NAVA. Ventilation contribution of the dependent lung region was equally in balance with the non-dependent lung region during PSV 5 cm H2O, NAVA 50 and 100 %. CONCLUSION: Neurally Adjusted Ventilatory Assist ventilation had a beneficial effect on the ventilation of the dependent lung region and showed less over-assistance compared to PSV in patients with ALI.

Episodic memory impairment in frontotemporal dementia; a 99mTc- HMPAO SPECT study.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the most common types of dementia in the presenile population. Episodic memory impairment, the clinical hallmark of AD, can also be encountered in patients with FTD, complicating accurate diagnosis. Several studies in FTD have correlated memory deficits with neuroimaging findings, but lacked to compare neuroimaging results in FTD patients with and without memory impairment, while this latter analysis may give us insight into the underlying mechanisms of memory impairment in FTD. The aim of the present study was to compare (99m)Tc-HMPAO SPECT hypoperfusion patterns between FTD with episodic memory impairment (n = 13), FTD patients without episodic memory impairment (n = 10) as well as early onset (< 70 yrs) AD patients (n = 13), and controls (n = 15). We performed our analyses by means of Statistical Parametric Mapping software (SPM5), and showed that FTD patients with episodic memory impairment had lower perfusion in the right temporal lobe compared with FTD patients without memory impairment. Lower perfusion in this region correlated with worse memory performance on the Clinical Dementia Rating scale in FTD patients. With equal performances on memory tests, patients with early onset AD showed posterior temporal and parietal lobe hypoperfusion in comparison with patients with FTD and memory impairment, while vice versa hypoperfusion in the anterior frontotemporal regions was found in FTD patients with memory impairment in comparison with AD.

Midcingulate involvement in progressive supranuclear palsy and tau positive frontotemporal dementia.

BACKGROUND: Progressive supranuclear palsy (PSP) patients often exhibit cognitive decline and behavioural changes during the disease course. In a subset, these symptoms may be the presenting manifestation and can be similar to those in frontotemporal dementia (FTD). However, correlation studies between quantitative imaging measures and detailed neuropsychological assessment are scarce. The aim of this study was to investigate the functional role of affected brain regions in cognition in PSP compared with controls and subsequently examine these regions in FTD patients with known tau pathology (FTD tau). METHODS: 21 PSP patients, 27 healthy controls and 11 FTD tau patients were enrolled. All participants underwent neuropsychological testing and technetium-99m-hexamethyl-propylenamine-oxime single photon emission CT. Regression slope analyses were performed in statistical parametric mapping to find significant associations between neuropsychological test results and brain perfusion. RESULTS: PSP patients showed hypoperfusion in the midcingulate cortex (MCC) of which the posterior part correlated with Stroop III and Weigl. In FTD tau patients, MCC involvement was located more anterior and correlated with Stroop III and Wisconsin Card Sorting Test concepts. The degree of hypoperfusion in the anterior cortex and MCC in the disorders differed in the subgenual anterior cingulate cortex only. CONCLUSIONS: The posterior part of the MCC is prominently involved in the neurodegenerative process of PSP, and the severity of its hypoperfusion correlated with the extent of executive dysfunction. In FTD tau, this cognitive domain was associated with anterior MCC involvement. The degree of hypoperfusion in these regions did not differ between PSP and FTD tau. These observations provide insight into the role of the cingulate cortex in cognitive dysfunction in these neurodegenerative disorders and warrant further investigations.

Intracranial pressure, brain PCO2, PO2, and pH during hypo- and hyperventilation at constant mean airway pressure in pigs.

OBJECTIVE: To evaluate in healthy, non-brain-traumatized animals the effects of hypo- and hyperventilation on intracranial pressure (ICP) and brain carbon dioxide, oxygen, and pH during the use of a ventilatory mode at constant mean airway pressure (MAwP). DESIGN AND SETTING: Prospective animal study in a university laboratory. SUBJECTS: Eight crossbred Landrace/Yorkshire pigs. INTERVENTIONS: The animals were ventilated in a pressure-controlled mode according to the open lung concept with an inspired oxygen fraction of 1.0. Starting at normoventilation, a stepwise hypo- and hyperventilation was performed to PaCO2 values of 90.4+/-10.4 and 26.9+/-4.1 mmHg, respectively. The ICP and brain parenchyma values [carbon dioxide (PbrCO2), oxygen (PbrO2), and pH (brpH)] measured by multiparameter sensors were recorded continuously during these maneuvres. RESULTS: During hypoventilation there was a significant increase in PbrCO2 tension, PbrO2 tension, and ICP. During hyperventilation there was a significant decrease in PbrCO2 tension and ICP while the change in PbrO2 was not significant. MAwP was kept stable during the stepwise hypo- and hyperventilation, and this resulted in a constant mean arterial pressure. CONCLUSIONS: Controlled hypo- and hyperventilation at constant MAwP in non-brain-traumatized pigs appears to induce changes in ICP and cerebral perfusion pressure which, however, do not necessarily lead to cerebral ischemia. To achieve adequate cerebral perfusion at an increased ICP level due to hypoventilation one must maintain sufficient arterial blood pressure. Hypercapnia resulted in a significant increase in brain oxygenation; however, this does not necessarily mean that permissive hypercapnia is neuroprotective.