Bioelectrical impedance analysis to assess hydration in critically ill patients: A practical guide demonstrating its use on artificially ventilated COVID patients.

Determining body contents such as body water volume and body cell mass have significant uses in health and disease. Accumulation of extracellular water is particularly difficult to monitor using classical methods. Bioelectrical impedance analysis (BIA) is a simple, rapid, and noninvasive method, based on the principle that the flow of altering electrical current through a particular tissue differs depending on the content of water and electrolytes. It is thus able to measure body composition, including total body and extracellular water. Although bioimpedance holds up quite well compared to the gold standard that is dual-energy X-ray, it has certain limitations in critically ill patients. Specifically, it cannot distinguish between intravascular and interstitial volume in the extracellular compartment, and as it employs equations based on population measurement, compositions can diverge significantly with severe overhydration or in the morbidly obese. Bioelectrical vector analysis (BIVA) does not use the calculations and is part of the measurements in newer multifrequency bioimpedance devices. There is growing evidence of the adverse effect of overhydration in critically ill patients and bioimpedance can be used to monitor hydration, but there is no information on how to use this method for bedside monitoring in practice. In this review we present a practical approach to Phase angle and BIA/BIVA interpretations for monitoring hydration status and rapid loss of skeletal muscle mass and their clinical use, on a cohort of critical COVID patients under artificial lung ventilation.

Siderophore-Based Noninvasive Differentiation of Aspergillus fumigatus Colonization and Invasion in Pulmonary Aspergillosis.

Germination from conidia to hyphae and hyphal propagation of Aspergillus fumigatus are the key pathogenic steps in the development of invasive pulmonary aspergillosis (IPA). By applying in vitro observations in a clinical study of 13 patients diagnosed with probable IPA, here, we show that the transition from colonization to the A. fumigatus invasive stage is accompanied by the secretion of triacetylfusarinine C (TafC), triacetylfusarinine B (TafB), and ferricrocin (Fc) siderophores into urine, with strikingly better sensitivity performance than serum sampling. The best-performing index, the TafC/creatinine index, with a median value of 17.2, provided 92.3% detection sensitivity (95% confidence interval [CI], 64.0 to 99.8%) and 100% specificity (95% CI, 84.6 to 100%), i.e., substantially better than the corresponding indications provided by galactomannan (GM) and ß-d-glucan (BDG) serology. For the same patient cohort, the serum GM and BDG sensitivities were 46.2 and 76.9%, respectively, and their specificities were 86.4 and 63.6%, respectively. The time-dependent specific appearance of siderophores in the host's urine represents an impactful clinical diagnostic advantage in the early discrimination of invasive aspergillosis from colonization. A favorable concentration of TafC in a clinical specimen distant from a deep infection site enables the noninvasive sampling of patients suffering from IPA. IMPORTANCE The importance of this research lies in the demonstration that siderophore analysis can distinguish between asymptomatic colonization and invasive pulmonary aspergillosis. We found clear associations between phases of fungal development, from conidial germination to the proliferative stage of invasive aspergillosis, and changes in secondary metabolite secretion. The critical extracellular fungal metabolites triacetylfusarinines C and B are produced during the polarized germination or postpolarized growth phase and reflect the morphological status of the proliferating pathogen. False positivity in Aspergillus diagnostics is minimized as mammalian cells do not synthesize Aspergillus siderophore or mycotoxin molecules.

Distinguishing Invasive from Chronic Pulmonary Infections: Host Pentraxin 3 and Fungal Siderophores in Bronchoalveolar Lavage Fluids.

The multiple forms of pulmonary aspergillosis caused by Aspergillus species are the most common respiratory mycoses. Although invasive, the analysis of diagnostic biomarkers in bronchoalveolar lavage fluid (BALF) is a clinical standard for diagnosing these conditions. The BALF samples from 22 patients with proven or probable aspergillosis were assayed for human pentraxin 3 (Ptx3), fungal ferricrocin (Fc), and triacetylfusarinine C (TafC) in a retrospective study. The infected group included patients with invasive pulmonary aspergillosis (IPA) and chronic aspergillosis (CPA). The BALF data were compared to a control cohort of 67 patients with invasive pulmonary mucormycosis (IPM), non-Aspergillus colonization, or bacterial infections. The median Ptx3 concentrations in patients with and without aspergillosis were 4545.5 and 242.0 pg/mL, respectively (95% CI, p < 0.05). The optimum Ptx3 cutoff for IPA was 2545 pg/mL, giving a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 100, 98, 95, and 100%, respectively. The median Ptx3 concentration for IPM was high at 4326 pg/mL. Pentraxin 3 assay alone can distinguish IPA from CPA and invasive fungal disease from colonization. Combining Ptx3 and TafC assays enabled the diagnostic discrimination of IPM and IPA, giving a specificity and PPV of 100%.

Molecular Mechanisms Underlying Intensive Care Unit-Acquired Weakness and Sarcopenia.

Skeletal muscle is a highly adaptable organ, and its amount declines under catabolic conditions such as critical illness. Aging is accompanied by a gradual loss of muscle, especially when physical activity decreases. Intensive care unit-acquired weakness is a common and highly serious neuromuscular complication in critically ill patients. It is a consequence of critical illness and is characterized by a systemic inflammatory response, leading to metabolic stress, that causes the development of multiple organ dysfunction. Muscle dysfunction is an important component of this syndrome, and the degree of catabolism corresponds to the severity of the condition. The population of critically ill is aging; thus, we face another negative effect-sarcopenia-the age-related decline of skeletal muscle mass and function. Low-grade inflammation gradually accumulates over time, inhibits proteosynthesis, worsens anabolic resistance, and increases insulin resistance. The cumulative consequence is a gradual decline in muscle recovery and muscle mass. The clinical manifestation for both of the above conditions is skeletal muscle weakness, with macromolecular damage, and a common mechanism-mitochondrial dysfunction. In this review, we compare the molecular mechanisms underlying the two types of muscle atrophy, and address questions regarding possible shared molecular mechanisms, and whether critical illness accelerates the aging process.

Expression and 7-day time course of circulating microRNAs in septic patients treated with nephrotoxic antibiotic agents.

BACKGROUND: Through regulation of signaling pathways, microRNAs (miRNAs) can be involved in sepsis and associated organ dysfunction. The aims of this study were to track the 7-day time course of blood miRNAs in patients with sepsis treated with vancomycin, gentamicin, or a non-nephrotoxic antibiotic and miRNA associations with neutrophil gelatinase-associated lipokalin (NGAL), creatinine, procalcitonin, interleukin-6, and acute kidney injury (AKI) stage. METHODS: Of 46 adult patients, 7 were on vancomycin, 20 on gentamicin, and 19 on another antibiotic. Blood samples were collected on days 1, 4, and 7 of treatment, and miRNAs were identified using quantitative reverse transcription PCR. RESULTS: The results showed no relationship between miRNA levels and biochemical variables on day 1. By day 7 of gentamicin treatment miR-15a-5p provided good discrimination between AKI and non-AKI (area under curve, 0.828). In patients taking vancomycin, miR-155-5p and miR-192-5p positively correlated with creatinine and NGAL values, and miR-192-5p and miR-423-5p positively correlated with procalcitonin and interleukin-6 in patients treated with a non-nephrotoxic antibiotic. In patients together we found positive correlation between miR-155-5p and miR-423-5p and all biochemical markers. CONCLUSION: The results suggest that these four miRNAs may serve as diagnostic or therapeutic tool in sepsis, renal injury and nephrotoxic treatment. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT04991376 . Registered on 27 July 2021.

Combined Use of Presepsin and (1,3)-ß-D-glucan as Biomarkers for Diagnosing Candida Sepsis and Monitoring the Effectiveness of Treatment in Critically Ill Patients.

New biomarker panel was developed and validated on 165 critically ill adult patients to enable a more accurate invasive candidiasis (IC) diagnosis. Serum levels of the panfungal biomarker (1,3)-ß-D-glucan (BDG) and the inflammatory biomarkers C-reactive protein, presepsin (PSEP), and procalcitonin (PCT) were correlated with culture-confirmed candidemia or bacteremia in 58 and 107 patients, respectively. The diagnostic utility was evaluated in sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). BDG was the best marker for IC, achieving 96.6% sensitivity, 97.2% specificity, 94.9% PPV, and 98.1% NPV at a cut-off of 200 pg/mL (p ≤ 0.001). PSEP exhibited 100% sensitivity and 100% NPV at a cut-off of 700 pg/mL but had a lower PPV (36.5%) and low specificity (5.6%). Combined use of PSEP and BDG, thus, seems to be the most powerful laboratory approach for diagnosing IC. Furthermore, PSEP was more accurate for 28-day mortality prediction the area under the receiver operating characteristic curve (AUC = 0.74) than PCT (AUC = 0.31; PCT cut-off = 0.5 ng/mL). Finally, serum PSEP levels decreased significantly after only 14 days of echinocandin therapy (p = 0.0012). The probability of IC is almost 100% in critically ill adults with serum BDG and PSEP concentrations > 200 pg/mL and >700 pg/mL, respectively, defining a borderline between non-invasive superficial Candida colonization and IC.

Tryptophan: A Unique Role in the Critically Ill.

Tryptophan is an essential amino acid whose metabolites play key roles in diverse physiological processes. Due to low reserves in the body, especially under various catabolic conditions, tryptophan deficiency manifests itself rapidly, and both the serotonin and kynurenine pathways of metabolism are clinically significant in critically ill patients. In this review, we highlight these pathways as sources of serotonin and melatonin, which then regulate neurotransmission, influence circadian rhythm, cognitive functions, and the development of delirium. Kynurenines serve important signaling functions in inter-organ communication and modulate endogenous inflammation. Increased plasma kynurenine levels and kynurenine-tryptophan ratios are early indicators for the development of sepsis. They also influence the regulation of skeletal muscle mass and thereby the development of polyneuromyopathy in critically ill patients. The modulation of tryptophan metabolism could help prevent and treat age-related disease with low grade chronic inflammation as well as post intensive care syndrome in all its varied manifestations: cognitive decline (including delirium or dementia), physical impairment (catabolism, protein breakdown, loss of muscle mass and tone), and mental impairment (depression, anxiety or post-traumatic stress disorder).

Noninvasive Combined Diagnosis and Monitoring of Aspergillus and Pseudomonas Infections: Proof of Concept.

In acutely ill patients, particularly in intensive care units or in mixed infections, time to a microbe-specific diagnosis is critical to a successful outcome of therapy. We report the application of evolving technologies involving mass spectrometry to diagnose and monitor a patient's course. As proof of this concept, we studied five patients and used two rat models of mono-infection and coinfection. We report the noninvasive combined monitoring of Aspergillus fumigatus and Pseudomonas aeruginosa infection. The invasive coinfection was detected by monitoring the fungal triacetylfusarinine C and ferricrocin siderophore levels and the bacterial metabolites pyoverdin E, pyochelin, and 2-heptyl-4-quinolone, studied in the urine, endotracheal aspirate, or breath condensate. The coinfection was monitored by mass spectrometry followed by isotopic data filtering. In the rat infection model, detection indicated 100-fold more siderophores in urine compared to sera, indicating the diagnostic potential of urine sampling. The tools utilized in our studies can now be examined in large clinical series, where we could expect the accuracy and speed of diagnosis to be competitive with conventional methods and provide advantages in unraveling the complexities of mixed infections.

Nicotine replacement therapy in surgical patients.

BACKGROUND AND AIMS: The effect in smokers of nicotine withdrawal following surgery may contribute to the development of postoperative delirium. Nicotine is known to increase myocardial oxygen demand, coronary vasoconstriction, and may cause platelet activation leading to thrombosis. All of this can negatively impact postoperative recovery. The aim of this study was to determine whether nicotine replacement therapy can overweigh its negative effects, reduce the incidence of delirium, reduce the need for sedatives/analgesics, and/or shorten the duration of artificial pulmonary ventilation. METHODS: This prospective randomized single-blind study was performed in a 21-bed ICU. Fifty-two patients (26 intervention/ 26 control) met the inclusion criteria. Patients in the intervention group received a 21mg nicotine patch daily until discharged from the ICU (up to 7 days), patients in the control group received a placebo patch. The incidence of delirium was monitored with the CAM-ICU test. Sedatives/analgesics used in the ICU, and the duration of both artificial ventilation as well as total ICU stay were recorded for both groups. RESULTS: Nicotine replacement in smokers did not reduce the incidence of delirium in patients who had undergone surgery. Neither did it statistically significantly affect the length of hospitalization, sedation, analgesia, or vasopressors. CONCLUSION: This study did not confirm the effect of nicotine replacement therapy in reducing the incidence of delirium, it did not shorten the total duration of ICU stay or artificial ventilation and there was no reduced sedation requirement. We therefore saw no beneficial effect in patients receiving nicotine replacement therapy following elective surgery.

Serotonin-Its Synthesis and Roles in the Healthy and the Critically Ill.

Serotonin (5-hydroxytryptamine, 5-HT) plays two important roles in humans-one central and the other peripheral-depending on the location of the 5-HT pools of on either side of the blood-brain barrier. In the central nervous system it acts as a neurotransmitter, controlling such brain functions as autonomic neural activity, stress response, body temperature, sleep, mood and appetite. This role is very important in intensive care, as in critically ill patients multiple serotoninergic agents like opioids, antiemetics and antidepressants are frequently used. High serotonin levels lead to altered mental status, deliria, rigidity and myoclonus, together recognized as serotonin syndrome. In its role as a peripheral hormone, serotonin is unique in controlling the functions of several organs. In the gastrointestinal tract it is important for regulating motor and secretory functions. Apart from intestinal motility, energy metabolism is regulated by both central and peripheral serotonin signaling. It also has fundamental effects on hemostasis, vascular tone, heart rate, respiratory drive, cell growth and immunity. Serotonin regulates almost all immune cells in response to inflammation, following the activation of platelets.

Hospital-acquired methemoglobinemia.

Methemoglobinemia is rare condition of hem iron. Ferrous form iron (Fe2+) is oxidised to Ferric form (Fe3+). Methemoglobin has reduced ability to release oxygen to tissues and thereby leads to tissue hypoxia. We present case of patient with methemoglobinemia of unknown etiology. Methemoglobinemia developed during hospitalization. Diferent causes of methemoglobinemia and also a treatment possibilities are discussed.

Acute Kidney Injury in Septic Patients Treated by Selected Nephrotoxic Antibiotic Agents-Pathophysiology and Biomarkers-A Review.

Acute kidney injury is a common complication in critically ill patients with sepsis and/or septic shock. Further, some essential antimicrobial treatment drugs are themselves nephrotoxic. For this reason, timely diagnosis and adequate therapeutic management are paramount. Of potential acute kidney injury (AKI) biomarkers, non-protein-coding RNAs are a subject of ongoing research. This review covers the pathophysiology of vancomycin and gentamicin nephrotoxicity in particular, septic AKI and the microRNAs involved in the pathophysiology of both syndromes. PubMED, UptoDate, MEDLINE and Cochrane databases were searched, using the terms: biomarkers, acute kidney injury, antibiotic nephrotoxicity, sepsis, miRNA and nephrotoxicity. A comprehensive review describing pathophysiology and potential biomarkers of septic and toxic acute kidney injury in septic patients was conducted. In addition, five miRNAs: miR-15a-5p, miR-192-5p, miR-155-5p, miR-486-5p and miR-423-5p specific to septic and toxic acute kidney injury in septic patients, treated by nephrotoxic antibiotic agents (vancomycin and gentamicin) were identified. However, while these are at the stage of clinical testing, preclinical and clinical trials are needed before they can be considered useful biomarkers or therapeutic targets of AKI in the context of antibiotic nephrotoxicity or septic injury.

Hypoxemia/hypoxia and new concepts of oxygen therapy in intensive care.

Oxygen is biologically vital element sustaining life. The tissue oxygen delivery is therefore precisely regulated. The degree of tissue oxygenation is estimated by measurement of oxygen blood level. The lack of oxygen on cellular and tissue level can lead to organ failure and life-threatening condition. Important adaptive processes are activated during the sublethal hypoxia with goal to preserve cellular and tissue functions. Inadequate effort to correct hypoxia can cause either disturbance of the adaptation or undesirable tissue hyperoxia. This fact is taken into account in two currently proposed concepts: (1) precise control of arterial oxemia and (2) permissive hypoxemia. Recent literature supports rather restrictive strategy of oxygen therapy in critical care.

[Duration of antibiotic therapy - How to shorten it?]

Broad spectrum antibiotics act against a wide range of disease-causing bacteria. However, their use may be associated with serious adverse reactions in patients. Inadequate antimicrobial treatment has been shown to increase mortality. Thus, it is essential to shorten the antibiotic treatment duration to the time necessary to fight the infection. The objectives of this review are to summarize the available options, controversies and evidence concerning the optimization of antibiotic therapy in ICUs; the options we have to achieve faster identification of the pathogen(s), to target the therapy, to use narrower spectrum antibiotics or to discontinue empirical antimicrobial treatment; and the options that are available to manage the treatment properly. Antibiotic de-escalation is a crucial strategy to minimize the risk of inadequate therapy as well as to decrease the risk of bacterial resistance development. Rapid tests and biomarkers may help to identify or rule out bacterial infections, helping clinicians to avoid unnecessary use of antibiotics and to shorten the treatment. These more accurate novel diagnostic tools can help us to improve patient outcomes.

Presepsin in the diagnostics of sepsis.

Sepsis remains one of the most common causes of death worldwide. It is caused by a complex of inadequate host responses to infection. It is also often difficult to distinguish sepsis from a non-infectious cause of systemic inflammatory response syndrome. Early identification of an infectious origin may dramatically help to improve the outcome and reduce mortality. That is the main reason why clinicians need fast, reliable and specific biomarkers for recognition of sepsis. Presepsin (sCD-14ST) is one of promising biomarkers, the level of which increases in response to a microbial infection in the host. As a glycoprotein expressed in the membranes of monocytes and macrophages, CD14 (cluster of differentiation 14) serves especially as a co-receptor of the lipopolysaccharide-lipopolysaccharide binding protein complexes, and activates the inflammatory cascade. Consequently, during the inflammatory reaction, sCD14-ST, known as presepsin, is cleaved away from plasma. The objective of this article is to determine the diagnostic value of presepsin in the diagnostics of sepsis, assessing its severity, and monitoring the effectiveness of therapeutic interventions, and to establish the prognostic value of this biomarker.

Exogenous surfactant as a bridge to prolonged "total lung rest" in severely injured patient during extracorporeal membrane oxygenation.

We report a case of a 20-year-old male patient suffering from motorcycle accident complicated by rapid development of severe refractory hypoxemia and hypercapnia due to serious bilateral lung contusions and lacerations. Positive pressure mechanical ventilation induced pressure-dependent massive air leak from disrupted pulmonary tissue. Simultaneous implementation of veno-venous extracorporeal membrane oxygenation together with surfactant application allowed prolonged disconnection of patient from mechanical ventilation ("total lung rest" mode). Despite considerable areas of nonaerated tissue on computed tomography prior to the disconnection from mechanical ventilation, almost total functional recovery of lungs was eventually achieved.

Incidence and risk factors for delirium development in ICU patients - a prospective observational study.

BACKGROUND AND AIMS: Delirium is an acute brain dysfunction and a frequent complication in critically ill patients. When present it significantly worsens the prognosis of patients. The aim of this study was to evaluate the incidence of delirium and risk factors for delirium in a mixed group of trauma, medical and surgical ICU patients. METHODS: A prospective observational study was conducted in one of the six-bed Intensive Care Units of the University Hospital Ostrava in the Czech Republic during a 12-month period. We evaluated the incidence of delirium and its predisposing and precipitating risk factors. All patients were assessed daily using the Confusion Assessment Method for the ICU (CAM-ICU). RESULTS AND CONCLUSIONS: Of the total of 332 patients with a median APACHE II (the Acute Physiology and Chronic Health Evaluation) score of 12, who were evaluated for delirium, 48 could not be assessed using CAM-ICU (47 due to prolonged coma, 1 due to language barriers). The incidence of delirium was 26.1%, with trauma and medical patients being more likely to develop delirium than surgical patients. Risk of delirium was significantly associated with age ≥ 65 years, and alcohol abuse in their anamnesis, with APACHE II score on admission, and with the use of sedatives and/or vasopressors. Delirious patients who remained in the ICU for a prolonged period showed a greater need for ventilator support and had a greater ICU-mortality.