Non-invasive assessment of stroke volume and cardiovascular parameters based on peripheral pressure waveform.

Cardiovascular diseases are the leading cause of death globally, making the development of non-invasive and simple-to-use tools that bring insights into the state of the cardiovascular system of utmost importance. We investigated the possibility of using peripheral pulse wave recordings to estimate stroke volume (SV) and subject-specific parameters describing the selected properties of the cardiovascular system. Peripheral pressure waveforms were recorded in the radial artery using applanation tonometry (SphygmoCor) in 35 hemodialysis (HD) patients and 14 healthy subjects. The pressure waveforms were then used to estimate subject-specific parameters of a mathematical model of pulse wave propagation coupled with the elastance-based model of the left ventricle. Bioimpedance cardiography measurements (PhysioFlow) were performed to validate the model-estimated SV. Mean absolute percentage error between the simulated and measured pressure waveforms was 4.0% and 2.8% for the HD and control group, respectively. We obtained a moderate correlation between the model-estimated and bioimpedance-based SV (r = 0.57, p<0.05, and r = 0.58, p<0.001, for the control group and HD patients, respectively). We also observed a correlation between the estimated end-systolic elastance of the left ventricle and the peripheral systolic pressure in both HD patients (r = 0.84, p<0.001) and the control group (r = 0.70, p<0.01). These preliminary results suggest that, after additional validation and possibly further refinement to increase accuracy, the proposed methodology could support non-invasive assessment of stroke volume and selected heart function parameters and vascular properties. Importantly, the proposed method could be potentially implemented in the existing devices measuring peripheral pressure waveforms.

Concentration of Apoptotic Factors in Bronchoalveolar Lavage Fluid, as Potential Brain-Lung Oxygen Relationship, Correspond to the Severity of Brain Injury.

BACKGROUND: The mechanism of acute brain injury initiates a cascade of consequences which can directly cause lung damage, and this can contribute to poor neurological outcomes. The aim of this study was to evaluate concentration of different apoptotic molecules in the bronchoalveolar lavage fluid (BALF) in patients after severe brain injury and to correlate them with selected clinical variables and mortality. METHODS: Patients with brain injury receiving BALF operation were included in the study. BALF samples were collected within the first 6-8 hours after traumatic brain injury (A) and at days 3 (B) and 7 (C) after admission to the intensive care unit (ICU). Changes in the BALF nuclear-encoded protein (Bax), apoptotic regulatory protein (Bcl-2), pro-apoptotic protein (p53) and its upregulated modulator (PUMA), apoptotic protease factor 1 (APAF-1), Bcl-2 associated agonist of cell death (BAD) and caspase-activated DNase (CAD) were analysed. These values were correlated with the selected oxygenation parameters, Rotterdam computed tomography (CT) score, the Glasgow Coma Score and 28-day mortality. RESULTS: We found a significant increase in the concentration of selected apoptotic factors at admission (A), at day 3 (B) and day 7 (C) after severe brain damage contrasted with baseline level A (p < 0.001, separately). That concentration of selected apoptotic factors was significantly correlated with the severity of the injury and mortality. CONCLUSIONS: Activation of different apoptotic pathways seems to be an important process occurring in the lungs of patients in the early phases after severe brain trauma. Levels of apoptotic factors in the BALF correlates with the severity of brain injury.

Humulus lupus extract rich in xanthohumol improves the clinical course in critically ill COVID-19 patients.

BACKGROUND: The systemic inflammatory response following severe COVID-19 is associated with poor outcomes. Several anti-inflammatory medications have been studied in COVID-19 patients. Xanthohumol (Xn), a natural extract from hop cones, possesses strong anti-inflammatory and antioxidative properties. The aim of this study was to analyze the effect of Xn on the inflammatory response and the clinical outcome of COVID-19 patients. METHODS: Adult patients treated for acute respiratory failure (PaO2/FiO2 less than 150) were studied. Patients were randomized into two groups: Xn - patients receiving adjuvant treatment with Xn at a daily dose of 4.5 mg/kg body weight for 7 days, and C - controls. Observations were performed at four time points: immediately after admission to the ICU and on the 3rd, 5th, and 7th days of treatment. The inflammatory response was assessed based on the plasma IL-6 concentration, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP) and D-dimer levels. The mortality rate was determined 28 days after admission to the ICU. RESULTS: Seventy-two patients were eligible for the study, and 50 were included in the final analysis. The mortality rate was significantly lower and the clinical course was shorter in the Xn group than in the control group (20% vs. 48%, p < 0.05, and 9 ± 3 days vs. 22 ± 8 days, p < 0.001). Treatment with Xn decreased the plasma IL-6 concentration (p < 0.01), D-dimer levels (p < 0.05) and NLR (p < 0.01) more significantly than standard treatment alone. CONCLUSION: Adjuvant therapy with Xn appears to be a promising anti-inflammatory treatment in COVID-19 patients.

Cerebral Oxygen Delivery and Consumption in Brain-Injured Patients.

Organism survival depends on oxygen delivery and utilization to maintain the balance of energy and toxic oxidants production. This regulation is crucial to the brain, especially after acute injuries. Secondary insults after brain damage may include impaired cerebral metabolism, ischemia, intracranial hypertension and oxygen concentration disturbances such as hypoxia or hyperoxia. Recent data highlight the important role of clinical protocols in improving oxygen delivery and resulting in lower mortality in brain-injured patients. Clinical protocols guide the rules for oxygen supplementation based on physiological processes such as elevation of oxygen supply (by mean arterial pressure (MAP) and intracranial pressure (ICP) modulation, cerebral vasoreactivity, oxygen capacity) and reduction of oxygen demand (by pharmacological sedation and coma or hypothermia). The aim of this review is to discuss oxygen metabolism in the brain under different conditions.

Melatonin and the Brain-Heart Crosstalk in Neurocritically Ill Patients-From Molecular Action to Clinical Practice.

Brain injury, especially traumatic brain injury (TBI), may induce severe dysfunction of extracerebral organs. Cardiac dysfunction associated with TBI is common and well known as the brain-heart crosstalk, which broadly refers to different cardiac disorders such as cardiac arrhythmias, ischemia, hemodynamic insufficiency, and sudden cardiac death, which corresponds to acute disorders of brain function. TBI-related cardiac dysfunction can both worsen the brain damage and increase the risk of death. TBI-related cardiac disorders have been mainly treated symptomatically. However, the analysis of pathomechanisms of TBI-related cardiac dysfunction has highlighted an important role of melatonin in the prevention and treatment of such disorders. Melatonin is a neurohormone released by the pineal gland. It plays a crucial role in the coordination of the circadian rhythm. Additionally, melatonin possesses strong anti-inflammatory, antioxidative, and antiapoptotic properties and can modulate sympathetic and parasympathetic activities. Melatonin has a protective effect not only on the brain, by attenuating its injury, but on extracranial organs, including the heart. The aim of this study was to analyze the molecular activity of melatonin in terms of TBI-related cardiac disorders. Our article describes the benefits resulting from using melatonin as an adjuvant in protection and treatment of brain injury-induced cardiac dysfunction.

The Connection Between Selected Caspases Levels in Bronchoalveolar Lavage Fluid and Severity After Brain Injury.

Objective: The interaction between the brain and lungs has been the subject of many clinical reports, while the exact impact of brain injury on the physiology of the respiratory system is still subject to numerous experimental studies. The purpose of this study was to investigate the activation of selected caspases levels in bronchoalveolar lavage fluid (mini BALF) of patients after isolated brain injury and their correlation with the severity of the injury. Methods: The analysis was performed on patients who were admitted to the intensive care unit (ICU) for severe isolated brain injury from March 2018 to April 2020. All patients were intubated and mechanically ventilated. Mini BALF was collected within the first 6-8 h after trauma and on days 3 and 7 after admission. The concentrations of selected caspases were determined and correlated with the severity of brain injury evaluated by the Rotterdam CT Score, Glasgow Coma Score, and 28-day mortality. Results: Our results showed significantly elevated levels of selected caspases on days 3 and 7 after brain injury, and revealed apoptosis activation during the first 7 days after brain trauma. We found a significant different correlation between the elevation of selected caspases 3, 6, 8, and 9, and the Glasgow Coma Score, Rotterdam CT scale, and 28-day mortality. Conclusions: The increased levels of selected caspases in the mini BALF in our patients indicate an intensified activation of apoptosis in the lungs, which is related to brain injury itself via various apoptotic pathways and correlates with the severity of brain injury.

Credibility of the Neutrophil-to-Lymphocyte Count Ratio in Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide. The consequences of a TBI generate the activation and accumulation of inflammatory cells. The peak number of neutrophils entering into an injured brain is observed after 24 h; however, cells infiltrate within 5 min of closed brain injury. Neutrophils release toxic molecules including free radicals, proinflammatory cytokines, and proteases that advance secondary damage. Regulatory T cells impair T cell infiltration into the central nervous system and elevate reactive astrogliosis and interferon-γ gene expression, probably inducing the process of healing. Therefore, the neutrophil-to-lymphocyte ratio (NLR) may be a low-cost, objective, and available predictor of inflammation as well as a marker of secondary injury associated with neutrophil activation. Recent studies have documented that an NLR value on admission might be effective for predicting outcome and mortality in severe brain injury patients.

Suppression of Electrographic Seizures Is Associated with Amelioration of QTc Interval Prolongation in Patients with Traumatic Brain Injury.

INTRODUCTION: Disorders in electroencephalography (EEG) are commonly noted in patients with traumatic brain injury (TBI) and may be associated with electrocardiographic disturbances. Electrographic seizures (ESz) are the most common features in these patients. This study aimed to explore the relationship between ESz and possible changes in QTc interval and spatial QRS-T angle both during ESz and after ESz resolution. METHODS: Adult patients with TBI were studied. Surface 12-lead ECGs were recorded using a Cardiax device during ESz events and 15 min after their effective suppression using barbiturate infusion. The ESz events were diagnosed using Masimo Root or bispectral index (BIS) devices. RESULTS: Of the 348 patients considered for possible inclusion, ESz were noted in 72, with ECG being recorded in 21. Prolonged QTc was noted during ESz but significantly ameliorated after ESz suppression (540.19 ± 60.68 ms vs. 478.67 ± 38.52 ms, p < 0.001). The spatial QRS-T angle was comparable during ESz and after treatment. Regional cerebral oximetry increased following ESz suppression (from 58.4% ± 6.2 to 60.5% ± 4.2 (p < 0.01) and from 58.2% ± 7.2 to 60.8% ± 4.8 (p < 0.05) in the left and right hemispheres, respectively). CONCLUSION: QTc interval prolongation occurs during ESz events in TBI patients but both it and regional cerebral oximetry are improved after suppression of seizures.

Why is it worth remembering the lung microbiome in ICU patients?

In recent years commensal microorganisms are not just "passive occupants", but important element of homeostasis. There are numerous reports documenting the composition and role of the gut, skin or vagina microbiome but the role of commensal orga-nisms living in the lungs is relatively unknown. Pulmonary microbiome impact on the immune response of the host organism and may indicate new therapeutic directions. Lung microbiome, by modulating the expression of innate immunity genes, causes an increase in the concentration of interleukin (IL)-5, IL-10, interferon γ and C-C motif chemokine ligand 11, affects the toll-like receptor-4-dependent response of pulmonary macrophages and modulate the production of antibacterial peptides contained in the mucus. It is documented that disorders of the lung microbiome contribute to asthma or chronic obstructive pulmonary disease. However it is known that pulmonary dysbiosis also occurs in critically ill patients. It is possible, therefore, that microbiota-targeted therapy may constitute the future therapeutic direction in ICU.

Potentially Detrimental Effects of Hyperosmolality in Patients Treated for Traumatic Brain Injury.

Hyperosmotic therapy is commonly used to treat intracranial hypertension in traumatic brain injury patients. Unfortunately, hyperosmolality also affects other organs. An increase in plasma osmolality may impair kidney, cardiac, and immune function, and increase blood-brain barrier permeability. These effects are related not only to the type of hyperosmotic agents, but also to the level of hyperosmolality. The commonly recommended osmolality of 320 mOsm/kg H2O seems to be the maximum level, although an increase in plasma osmolality above 310 mOsm/kg H2O may already induce cardiac and immune system disorders. The present review focuses on the adverse effects of hyperosmolality on the function of various organs.

Usefulness of Cerebral Oximetry in TBI by NIRS.

Measurement of cerebral oximetry by near-infrared spectroscopy provides continuous and non-invasive information about the oxygen saturation of haemoglobin in the central nervous system. This is especially important in the case of patients with traumatic brain injuries. Monitoring of cerebral oximetry in these patients could allow for the diagnosis of inadequate cerebral oxygenation caused by disturbances in cerebral blood flow. It could enable identification of episodes of hypoxia and cerebral ischemia. Continuous bedside measurement could facilitate the rapid diagnosis of intracranial bleeding or cerebrovascular autoregulation disorders and accelerate the implementation of treatment. However, it should be remembered that the method of monitoring cerebral oximetry by means of near-infrared spectroscopy also has its numerous limitations, resulting mainly from its physical properties. This paper summarizes the usefulness of monitoring cerebral oximetry by near-infrared spectroscopy in patients with traumatic brain injury, taking into account the advantages and the disadvantages of this technique.

Mechanical ventilation in neurocritical care setting: A clinical approach.

Neuropatients often require invasive mechanical ventilation (MV). Ideal ventilator settings and respiratory targets in neuro patients are unclear. Current knowledge suggests maintaining protective tidal volumes of 6-8 ml/kg of predicted body weight in neuropatients. This approach may reduce the rate of pulmonary complications, although it cannot be easily applied in a neuro setting due to the need for special care to minimize the risk of secondary brain damage. Additionally, the weaning process from MV is particularly challenging in these patients who cannot control the brain respiratory patterns and protect airways from aspiration. Indeed, extubation failure in neuropatients is very high, while tracheostomy is needed in one-third of the patients. The aim of this manuscript is to review and describe the current management of invasive MV, weaning, and tracheostomy for the main four subpopulations of neuro patients: traumatic brain injury, acute ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage.

Intra-abdominal hypertension and hypoxic respiratory failure together predict adverse outcome - A sub-analysis of a prospective cohort.

PURPOSE: To assess whether the combination of intra-abdominal hypertension (IAH, intra-abdominal pressure ≥ 12 mmHg) and hypoxic respiratory failure (HRF, PaO2/FiO2 ratio < 300 mmHg) in patients receiving invasive ventilation is an independent risk factor for 90- and 28-day mortality as well as ICU- and ventilation-free days. METHODS: Mechanically ventilated patients who had blood gas analyses performed and intra-abdominal pressure measured, were included from a prospective cohort. Subgroups were defined by the absence (Group 1) or the presence of either IAH (Group 2) or HRF (Group 3) or both (Group 4). Mixed-effects regression analysis was performed. RESULTS: Ninety-day mortality increased from 16% (Group 1, n = 50) to 30% (Group 2, n = 20) and 27% (Group 3, n = 100) to 49% (Group 4, n = 142), log-rank test p < 0.001. The combination of IAH and HRF was associated with increased 90- and 28-day mortality as well as with fewer ICU- and ventilation-free days. The association with 90-day mortality was no longer present after adjustment for independent variables. However, the association with 28-day mortality, ICU- and ventilation-free days persisted after adjusting for independent variables. CONCLUSIONS: In our sub-analysis, the combination of IAH and HRF was not independently associated with 90-day mortality but independently increased the odds of 28-day mortality, and reduced the number of ICU- and ventilation-free days.

Changes in Subendocardial Viability Ratio in Traumatic Brain Injury Patients.

Background: Traumatic brain injury (TBI) is often associated with cardiac dysfunction, which is a consequence of the brain-heart cross talk. The subendocardial viability ratio (SEVR) is an estimate of myocardial perfusion. The aim of this study was to analyze changes in the SEVR in patients with severe TBI without previous cardiac diseases. Methods: Adult patients treated for severe TBI with a Glasgow coma score <8 were studied. Pressure waveforms were obtained by a high-fidelity tonometer in the radial artery for SEVR calculation at five time points: immediately after admission to the intensive care unit and 24, 48, 72, and 96 h after admission. SEVRs and other clinically important parameters were analyzed in patients who survived and did not survive after 28 days of treatment, as well as in patients who underwent decompressive craniectomy (DC). Results: A total of 64 patients (16 females and 48 males) aged 18-64 years were included. Fifty patients survived and 14 died. DC was performed in 23 patients. SEVRs decreased 24 h after admission in nonsurvivors (p < 0.05) and after 48 h in survivors (p < 0.01) and its values were significantly lower in nonsurvivors than in survivors at 24, 72, and 96 h from admission (p < 0.05). The SEVR increased following DC (p < 0.05). Conclusions: A decreased SEVR is observed in TBI patients. Surgical decompression increases the SEVR, indicating improvement in coronary microvascular perfusion. The results of our study seem to confirm that brain injury affects myocardium function.

Novel Synthetic and Natural Therapies for Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major cause of disability and death worldwide. The initial mechanical insult results in tissue and vascular disruption with hemorrhages and cellular necrosis that is followed by dynamic secondary brain damage that presumably results in additional destruction of the brain. In order to minimize deleterious consequences of the secondary brain damage- such as inflammation, bleeding or reduced oxygen supply. The old concept of the -staircase approach- has been updated in recent years by most guidelines and should be followed as it is considered the only validated approach for the treatment of TBI. Besides, a variety of novel therapies have been proposed as neuroprotectants. The molecular mechanisms of each drug involved in the inhibition of secondary brain injury can result as a potential target for the early and late treatment of TBI. However, no specific recommendation is available on their use in the clinical setting. The administration of both synthetic and natural compounds, which act on specific pathways involved in the destructive processes after TBI, even if usually employed for the treatment of other diseases, can show potential benefits. This review represents a massive effort towards current and novel therapies for TBI that have been investigated in both pre-clinical and clinical settings. This review aims to summarize the advancement in therapeutic strategies based on specific and distinct -target of therapies-: brain edema, ICP control, neuronal activity and plasticity, anti-inflammatory and immunomodulatory effects, cerebral autoregulation, antioxidant properties, and future perspectives with the adoption of mesenchymal stromal cells.

The Brain-gut Axis-where are we now and how can we Modulate these Connections?

A traumatic brain injury (TBI) initiates an inflammatory response with molecular cascades triggered by the presence of necrotic debris, including damaged myelin, hemorrhages and injured neuronal cells. Molecular cascades prominent in TBI-induced inflammation include the release of an excess of proinflammatory cytokines and angiogenic factors, the degradation of tight junctions (TJs), cytoskeletal rearrangements and leukocyte and protein extravasation promoted by increased expression of adhesion molecules. The brain-gut axis consists of a complex network involving neuroendocrine and immunological signaling pathways and bi-directional neural mechanisms. Importantly, modifying the gut microbiome alters this axis, and in turn may influence brain injury and neuroinflammatory processes. In recent years it has been demonstrated that the activity and composition of the gastrointestinal (GI) microbiome population influences the brain through all of above-mentioned pathways affecting homeostasis of the central nervous system (CNS). The GI microbiome is involved in the modulation of cellular and molecular processes which are fundamental to the progression of TBI-induced pathologies, including neuroinflammation, abnormal blood brain barrier (BBB) permeability, immune system responses, microglial activation, and mitochondrial dysfunction. It has been postulated that interaction between the brain and gut microbiome occurs mainly via the enteric nervous system and the vagus nerve through neuroactive compounds including serotonin or dopamine and activation by bacterial metabolites including endotoxin, neurotransmitters, neurotrophic factors, and cytokines. In recent years the multifactorial impact of selected immunomodulatory drugs on immune processes occurring in the CNS and involving the brain-gut axis has been under intensive investigation.

Pathophysiology and clinical consequences of arterial blood gases and pH after cardiac arrest.

Post cardiac arrest syndrome is associated with high morbidity and mortality, which is related not only to a poor neurological outcome but also to respiratory and cardiovascular dysfunctions. The control of gas exchange, and in particular oxygenation and carbon dioxide levels, is fundamental in mechanically ventilated patients after resuscitation, as arterial blood gases derangement might have important effects on the cerebral blood flow and systemic physiology.In particular, the pathophysiological role of carbon dioxide (CO2) levels is strongly underestimated, as its alterations quickly affect also the changes of intracellular pH, and consequently influence metabolic energy and oxygen demand. Hypo/hypercapnia, as well as mechanical ventilation during and after resuscitation, can affect CO2 levels and trigger a dangerous pathophysiological vicious circle related to the relationship between pH, cellular demand, and catecholamine levels. The developing hypocapnia can nullify the beneficial effects of the hypothermia. The aim of this review was to describe the pathophysiology and clinical consequences of arterial blood gases and pH after cardiac arrest.According to our findings, the optimal ventilator strategies in post cardiac arrest patients are not fully understood, and oxygen and carbon dioxide targets should take in consideration a complex pattern of pathophysiological factors. Further studies are warranted to define the optimal settings of mechanical ventilation in patients after cardiac arrest.

Decompressive Craniectomy Improves QTc Interval in Traumatic Brain Injury Patients.

BACKGROUND: Traumatic brain injury (TBI) is commonly associated with cardiac dysfunction, which may be reflected by abnormal electrocardiograms (ECG) and/or contractility. TBI-related cardiac disorders depend on the type of cerebral injury, the region of brain damage and the severity of the intracranial hypertension. Decompressive craniectomy (DC) is commonly used to reduce intra-cranial hypertension (ICH). Although DC decreases ICH rapidly, its effect on ECG has not been systematically studied. The aim of this study was to analyze the changes in ECG in patients undergoing DC. METHODS: Adult patients without previously known cardiac diseases treated for isolated TBI with DC were studied. ECG variables, such as: spatial QRS-T angle (spQRS-T), corrected QT interval (QTc), QRS and T axes (QRSax and Tax, respectively), STJ segment and the index of cardio-electrophysiological balance (iCEB) were analyzed before DC and at 12-24 h after DC. Changes in ECG were analyzed according to the occurrence of cardiac arrhythmias and 28-day mortality. RESULTS: 48 patients (17 female and 31 male) aged 18-64 were studied. Intra-cranial pressure correlated with QTc before DC (p < 0.01, r = 0.49). DC reduced spQRS-T (p < 0.001) and QTc interval (p < 0.01), increased Tax (p < 0.01) and changed STJ in a majority of leads but did not affect QRSax and iCEB. The iCEB was relatively increased before DC in patients who eventually experienced cardiac arrhythmias after DC (p < 0.05). Higher post-DC iCEB was also noted in non-survivors (p < 0.05), although iCEB values were notably heart rate-dependent. CONCLUSIONS: ICP positively correlates with QTc interval in patients with isolated TBI, and DC for relief of ICH reduces QTc and spQRS-T. However, DC might also increase risk for life-threatening cardiac arrhythmias, especially in ICH patients with notably prolonged QTc before and increased iCEB after DC.

Pathomechanisms of Non-Traumatic Acute Brain Injury in Critically Ill Patients.

Delirium, an acute alteration in mental status characterized by confusion, inattention and a fluctuating level of arousal, is a common problem in critically ill patients. Delirium prolongs hospital stay and is associated with higher mortality. The pathophysiology of delirium has not been fully elucidated. Neuroinflammation and neurotransmitter imbalance seem to be the most important factors for delirium development. In this review, we present the most important pathomechanisms of delirium in critically ill patients, such as neuroinflammation, neurotransmitter imbalance, hypoxia and hyperoxia, tryptophan pathway disorders, and gut microbiota imbalance. A thorough understanding of delirium pathomechanisms is essential for effective prevention and treatment of this underestimated pathology in critically ill patients.