Study protocol: understanding the pathophysiologic mechanisms underlying delirium in older people undergoing hip fracture surgery.

BACKGROUND: Postoperative delirium (POD) is a common complication of older people undergoing hip fracture surgery, which negatively affects clinical- and healthcare-related outcomes. Unfortunately, POD pathophysiology is still largely unknown, despite previous studies showing that neuroinflammation, neuroendocrine dysfunction, increased reactive oxidative stress (ROS), and endothelial dysfunctions may be involved. There is also evidence that many of the pathophysiological mechanisms which are involved in delirium are involved in sarcopenia too. This article describes the protocol of a pilot study to evaluate the feasibility of a larger one that will explore the pathophysiological mechanisms correlating POD with sarcopenia. We will analyse whether various biomarkers reflecting neuroinflammation, ROS, neuroendocrine disorders, and microvasculature lesions will be simultaneously expressed in in the blood, cerebrospinal fluid (CSF), and muscles of patients developing POD. METHODS: Two centres will be involved in this study, each recruiting a convenient sample of ten older patients with hip fracture. All of them will undergo a baseline Comprehensive Geriatric Assessment, which will be used to construct a Rockwood-based Frailty Index (FI). Blood samples will be collected for each patient on the day of surgery and 1 day before. Additionally, CSF and muscle fragments will be taken and given to a biologist for subsequent analyses. The presence of POD will be assessed in each patient every morning until hospital discharge using the 4AT. Delirium subtypes and severity will be assessed using the Delirium Motor Subtype Scale-4 and the Delirium-O-Meter, respectively. We will also evaluate the patient's functional status at discharge, using the Cumulated Ambulation Score. DISCUSSION: This study will be the first to correlate biomarkers of blood, CSF, and muscle in older patients with hip fracture.

Experimental assessment of an indirect method to measure the post-combustion flue gas flow rate in waste-to-energy plant based on multi-point measurements.

In waste-to-energy plants, the determination of the flue gas flow rate in the post-combustion section is of the utmost importance, e.g., for the verification of the compliance to the minimum residence time requirements (tres>2s) or for the control of flue gas treatment reactant injection, but the harsh conditions (high temperature and content of pollutants) do not allow for a direct measurement. The present work reports an experimental assessment of an indirect approach to estimate the flue gas flow rate in the post-combustion section of a rotary kiln plant with reduced uncertainty. This method consists on the direct measurement of the flow rate at a "colder" section of the plant (the boiler outlet) combined to the simultaneous measurements of flue gas composition measurements upstream and downstream of the boiler. From these measurements it is then possible to determine the mass of false air and to retrieve the actual flue gas flow-rate in the post-combustion chamber. A massive experimental campaign has been conducted at a full-scale medical waste incinerator, in which flue gas flow rate was estimated at different waste loads and ambient conditions. The results show that the percentage of false air can be significant and simply neglecting it can lead to substantial under-performance of the plant. Issues related to the practical implementation of the methods are illustrated in detail and the possibility to extend the methodology towards an online determination of post-combustion flue gas flow rate is discussed.

High efficiency particulate air filters and heat & moisture exchanger filters increase positive end-expiratory pressure in helmet continuous positive airway pressure: A bench-top study.

BACKGROUND: Helmet continuous positive airway pressure (CPAP) has been widely used during the COVID-19 pandemic. Specific filters (i.e. High Efficiency Particulate Air filter: HEPA; Heat & Moisture Exchanger Filter: HMEF) were used to prevent Sars-CoV2 environmental dispersion and were connected to the CPAP helmet. However, HEPA and HMEF filters may act as resistors to expiratory gas flow and increase the levels of pressure within the hood. METHODS: In a bench-top study, we investigated the levels of airway pressure generated by different HEPA and HMEF filters connected to the CPAP helmet in the absence of a Positive End Expiratory Pressure (PEEP) valve and with two levels of PEEP (5 and 10 cmH2O). All steps were performed using 3 increasing levels of gas flow (60, 80, 100 L/min). RESULTS: The use of 8 different commercially available filters significantly increased the pressure within the hood of the CPAP helmet with or without the use of PEEP valves. On average, the increase of pressure above the set PEEP ranged from 3 cmH2O to 10 cmH2O across gas flow rates of 60 to 100 L/min. The measure of airway pressure was highly correlated between the laboratory pressure transducer and the Helmet manometer. Bias with 95% Confidence Interval of Bias between the devices was 0.7 (-2.06; 0.66) cmH2O. CONCLUSIONS: The use of HEPA and HMEF filters placed before the PEEP valve at the expiratory port of the CPAP helmet significantly increase the levels of airway pressure compared to the set level of PEEP. The manometer can detect accurately the airway pressure in the presence of HEPA and HMEF filters in the helmet CPAP and its use should considered.

Measurement of end-expiratory lung volume by oxygen washin-washout in controlled and assisted mechanically ventilated patients.

OBJECTIVE: Assessing limits of agreement with helium dilution and repeatability of a new system (lung funcution, LUFU) that measures end-expiratory lung volume (EELV) in mechanically ventilated patients using the O(2) washin (EELV(Win)) and washout (EELV(Wout)) technique. LUFU consists of an Evita 4 ventilator, a side-stream oxygen analyzer, and a dedicated PC software. DESIGN AND SETTING: Prospective human study in a general ICU of a University hospital. PATIENTS: Thirty-six mechanically ventilated patients. INTERVENTIONS: We obtained 36 couples of both EELV(Win) and EELV(Wout) measurements in each patient (5 with healthy lungs, 9 with ALI, 22 with ARDS). Measurements were obtained with patients ventilated either by assisted (ASB, 16 measurements) or controlled (CMV, 20 measurements) ventilation. In 19 of 20 cases in CMV, we obtained helium dilution measurements (EELV(He)). MEASUREMENTS AND RESULTS: Bias for agreement with EELV(He) was -16 +/- 156 and 8 +/- 161 ml, respectively, for EELV(Win) and EELV(Wout). Bias for agreement between EELV(Win) and EELV(Wout) was 28 +/- 78 and 23 +/- 168 ml, respectively, for CMV and ASB. During CMV bias for repeatability were 8 +/- 92 and 23 +/- 165 ml, respectively, for EELV(Win) and EELV(Wout). During ASB bias for repeatability were 32 +/- 160 and -15 +/- 147 ml, respectively, for EELV(Win) and EELV(Wout). CONCLUSIONS: The LUFU method showed good agreement with helium, and good repeatability during partial and controlled mechanical ventilation. The technique is simple and safe.

A prospective international observational prevalence study on prone positioning of ARDS patients: the APRONET (ARDS Prone Position Network) study.

INTRODUCTION: While prone positioning (PP) has been shown to improve patient survival in moderate to severe acute respiratory distress syndrome (ARDS) patients, the rate of application of PP in clinical practice still appears low. AIM: This study aimed to determine the prevalence of use of PP in ARDS patients (primary endpoint), the physiological effects of PP, and the reasons for not using it (secondary endpoints). METHODS: The APRONET study was a prospective international 1-day prevalence study performed four times in April, July, and October 2016 and January 2017. On each study day, investigators in each ICU had to screen every patient. For patients with ARDS, use of PP, gas exchange, ventilator settings and plateau pressure (Pplat) were recorded before and at the end of the PP session. Complications of PP and reasons for not using PP were also documented. Values are presented as median (1st-3rd quartiles). RESULTS: Over the study period, 6723 patients were screened in 141 ICUs from 20 countries (77% of the ICUs were European), of whom 735 had ARDS and were analyzed. Overall 101 ARDS patients had at least one session of PP (13.7%), with no differences among the 4 study days. The rate of PP use was 5.9% (11/187), 10.3% (41/399) and 32.9% (49/149) in mild, moderate and severe ARDS, respectively (P = 0.0001). The duration of the first PP session was 18 (16-23) hours. Measured with the patient in the supine position before and at the end of the first PP session, PaO2/FIO2 increased from 101 (76-136) to 171 (118-220) mmHg (P = 0.0001) driving pressure decreased from 14 [11-17] to 13 [10-16] cmH2O (P = 0.001), and Pplat decreased from 26 [23-29] to 25 [23-28] cmH2O (P = 0.04). The most prevalent reason for not using PP (64.3%) was that hypoxemia was not considered sufficiently severe. Complications were reported in 12 patients (11.9%) in whom PP was used (pressure sores in five, hypoxemia in two, endotracheal tube-related in two ocular in two, and a transient increase in intracranial pressure in one). CONCLUSIONS: In conclusion, this prospective international prevalence study found that PP was used in 32.9% of patients with severe ARDS, and was associated with low complication rates, significant increase in oxygenation and a significant decrease in driving pressure.

Reynolds stress scaling in pipe flow turbulence-first results from CICLoPE.

This paper reports the first turbulence measurements performed in the Long Pipe Facility at the Center for International Cooperation in Long Pipe Experiments (CICLoPE). In particular, the Reynolds stress components obtained from a number of straight and boundary-layer-type single-wire and X-wire probes up to a friction Reynolds number of 3.8×104 are reported. In agreement with turbulent boundary-layer experiments as well as with results from the Superpipe, the present measurements show a clear logarithmic region in the streamwise variance profile, with a Townsend-Perry constant of A2≈1.26. The wall-normal variance profile exhibits a Reynolds-number-independent plateau, while the spanwise component was found to obey a logarithmic scaling over a much wider wall-normal distance than the other two components, with a slope that is nearly half of that of the Townsend-Perry constant, i.e. A2,w≈A2/2. The present results therefore provide strong support for the scaling of the Reynolds stress tensor based on the attached-eddy hypothesis. Intriguingly, the wall-normal and spanwise components exhibit higher amplitudes than in previous studies, and therefore call for follow-up studies in CICLoPE, as well as other large-scale facilities.This article is part of the themed issue 'Toward the development of high-fidelity models of wall turbulence at large Reynolds number'.

Changes in the excitability of the H-reflex in wrist flexors related to the prone or supine position of the forearm in man.

The effect of the forearm position, prone vs. supine, on the excitability of the H-reflex in flexor carpi radialis (FCR) muscle was tested in nine adult volunteers by comparing the recruitment profiles of the H and M waves. The H-reflex size, normalized to the maximal M response, was lower when the forearm was supine than when it was prone, with an average reduction of about 50% over most of the H-recruitment curve. In three wrist positions, intermediate between prone and supine, the amount of reflex attenuation was related to the prono-supination angle. Control experiments excluded that the changes in the H reflex excitability were due to displacements of the stimulating or recording electrodes.

[Angio-immunoblastic lymphadenopathy. Apropos of a clinical case]. / Linfoadenopatia angio-immunoblastica. A proposito di un caso clinico.

Reference is made to a personal case in an account of the clinical and pathological criteria that provide the diagnostic hinges of angio-immunoblastic lymphadenopathy. Stress is laid on the systemic and progressive nature of the disease, and support is given to the view that is an affection of the immuno-competent system. The fact that the course is unpredictable is seen as a reason for adopting an extremely cautions therapeutic approach based on corticosteroid hormones. Resort to the cytotoxic chemotherapeutical drugs customarily employed in other lymphoproliferative forms should be reserved for a few selected cases.

Long-term extracorporeal membrane oxygenation with minimal ventilatory support: a new paradigm for severe ARDS?

Pulmonary tuberculosis can lead to acute respiratory distress syndrome (ARDS) which is associated with high mortality. We report the case of a patient with pulmonary tuberculosis and severe ARDS (PaO2/FiO2<100 mmHg) who was initially managed with advanced up-to-date treatments (protective ventilation and extracorporeal membrane oxygenation, ECMO) but failed to improve. After a month of failure and the development of bilateral pneumothoraces, we drastically changed our therapeutic strategy: we maximized ECMO support to maintain oxygenation, we greatly reduced ventilation pressures and we left the pneumothoraces undrained. From then on, the patient improved and he eventually survived. This case suggests that ECMO permits large reductions in lung inflation and ventilation to rest the lungs, while maintaining acceptable oxygenation. The combination of ECMO and markedly attenuated ventilation strategy may be effective in cases of severe ARDS.

Positron emission tomography in ARDS: a new look at an old syndrome.

This is a review of some of the main findings obtained by positron emission tomography (PET) concerning the pathophysiology of acute respiratory distress syndrome (ARDS) and acute lung injury. PET (which is nowadays often combined with computed tomography) is a functional imaging technique based on the detection of a labeled molecule administered to a subject. Based on the molecule used, different lung functions can be imaged. Examples include inhaled, labeled nitrogen, which allows us to visualize regional aeration and ventilation, whereas lung perfusion has been studied by means of labeled water or by injected nitrogen dissolved in saline. With this latter technique, a global assessment of regional gas exchange is possible. Administration of [18F]FDG facilitates the imaging of cellular metabolic activity, reflecting an acute neutrophil-sustained inflammatory process. This technique has been used in experimental ARDS and, more recently, in patients. It showed, for example, that inflammatory activity of the lungs is markedly increased even in "normally aerated" regions at levels that are, in some cases, even higher than in the non-aerated regions.

Etiology of respiratory failure is related to mortality in critically ill patients affected by a hematological malignancy: a retrospective study.

AIM: The outcomes of patients affected by hematologic malignancies (HM) admitted to Intensive Care Units (ICUs) because of life-threatening complications are still considered to be poor. The aim of this study was to assess the incidence and impact of cardiac dysfunction on the outcome of these patients. METHODS: We retrospectively reviewed the records of the 48 patients (both adult and pediatric) with HM admitted in our ICU over the last four years, collecting data on admission diagnosis, type of HM, laboratory values and organ failure. RESULTS: All patients were admitted with respiratory failure. The overall mortality rate was 50% and the mortality rates were similar among patients with different types of HM. Septic shock and multiple organ failure were the leading causes of death. The overall incidence of cardiac dysfunction was high (31%). Interestingly, the ICU mortality of this subgroup was 27%, while the mortality of the rest of the population was 61% (p<0.05). CONCLUSIONS: ICU patients with HM have high mortality. Respiratory failure caused by cardiac dysfunction seems to be associated with a lower risk of death.

Time course of endogenous nitric oxide inhibitors in severe sepsis in humans.

AIM: Asymmetric and symmetric dimethylarginines (ADMA and SDMA, respectively) are protein breakdown markers; both compete with arginine for cellular transport and both are excreted in urine. Moreover, ADMA is a non-selective inhibitor of nitric oxide (NO) synthase that is metabolized by a specific hydrolase in which the activity during stress remains controversial. While an increase in ADMA is known to be associated with adverse events, little is known about SDMA. We investigated plasma ADMA and SDMA levels during ICU stay to reveal the time course of endogenous NO inhibition in patients with sepsis. METHODS: A post hoc analysis from a prospective random controlled trial conducted in three ICUs was performed to study the pathophysiological pathways of sepsis. ADMA, SDMA, the ratio of ADMA/SDMA (a marker of ADMA catabolism), arginine, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C reactive protein (CRP) were measured on days 1, 3, 6, 9, 12 and at discharge in 72 consecutive severely septic patients. RESULTS: Fasting basal glycemia, creatinine, IL-6, TNF-alpha, CRP, ADMA, and SDMA were higher than normal. The ADMA/SDMA ratio was decreased by 50%, and arginine levels were low. ADMA levels were related to the total Sequential Organ Failure Assessment (SOFA) scores and arginine levels, and inversely related to IL-6 and CRP levels. SDMA levels were related to Simplified Acute Physiologic Scores II (SAPS II), SOFA scores, blood urea, creatinine, and arginine levels. The ADMA/SDMA ratio was inversely related to IL-6 levels. In 58 ICU survivors, creatinine, IL-6, and CRP levels decreased over time; ADMA levels increased, SDMA levels remained stable, and the ADMA/SDMA ratio increased. In 14 non-survivors, creatinine, IL-6, TNF-alpha, CRP, and ADMA levels were stable, whereas the SDMA levels increased and the ADMA/SDMA ratio remained low. In both ICU survivors and non-survivors, the levels on the last ICU day confirmed the data trends. SDMA, but not ADMA, was associated with ICU mortality. CONCLUSION: ADMA catabolism appears to be activated by inflammation; its increase during the advanced septic phase in surviving patients may suggest an endogenous inhibition of NO synthesis during the full-blown septic phase. In severe sepsis, SDMA, but not ADMA, appears to be a marker of alterations in vital functions and mortality.

Which drugs for the control of fever in critical patients.

It has been estimated that nosocomial fever occurs in approximately one-third of hospitalized patients. The incidence is even higher in critically-ill patients in whom both infectious and noninfectious etiologies of fever are common. Polypeptide cytokines (endogenous pyrogens) such as interleukin-1b (IL-1b), tumor necrosis factor (TNF) and interleukin-6 (IL-6) act directly on the hypothalamus to effect a fever response by promoting an increase in heat generation and a decrease in heat loss. There is widespread acceptance that in most if not all critically ill neurologic patients fever should be treated but still it is not clear if fever per se in nonneurologic critically ill patients should be treated too. We review physical and pharmacological methods presently utilized to treat fever in critically ill patients.

Effects of recombinant human activated protein C on the fibrinolytic system of patients undergoing conventional or tight glycemic control.

AIM: Recombinant human activated protein C (rh-APC) and tight glycemic control (TGC) have been shown to reduce mortality in septic patients. Both interventions can reduce the plasma concentration and/or activity of the most powerful suppressor of fibrinolysis, plasminogen activator inhibitor-1 (PAI-1). Our aim was to evaluate the effects on the fibrinolytic system after the administration of rh-APC in septic patients undergoing conventional or TGC. METHODS: Posthoc analysis of data was collected from 90 patients with severe sepsis/septic shock, randomized to either conventional or TGC groups. Independent of these treatments, patients with at least two organ dysfunctions simultaneously received rh-APC. Plasma levels of multiple biochemical markers for fibrinolysis, coagulation, and inflammation were determined every day for the 1st week and then on study days 9, 11, 13, 18, 23, and 28. Clinical data and sepsis-related organ failure assessment (SOFA) scores were also recorded. RESULTS: Patients who had received rh-APC exhibited significantly more impairments in fibrinolysis at baseline (PAI-1 activity 49.76 [24.61-71.82] vs 21.92 [6.47-55-83] IU/mL, P=0.03). The reductions in plasma PAI-1 activity over time associated with rh-APC treatment were different according to whether the treatment was administered to patients undergoing conventional or TGC (P=0.01). However, the most prominent reductions were in patients undergoing conventional glycemic control. Significant interactions between the two study interventions were also found for PAI-1 concentration (P<0.001), C-reactive protein (P=0.02), and interleukin-6 levels (P<0.001). CONCLUSIONS: Both rh-APC and TGC appear to improve fibrinolysis in septic patients. The reduction in the impairment of fibrinolysis associated with rh-APC treatment seems greater in patients undergoing conventional glycemic control than in those undergoing TGC.

The use of helmets to deliver non-invasive continuous positive airway pressure in hypoxemic acute respiratory failure.

Non-invasive continuous positive airway pressure (CPAP) is a useful tool for managing patients with acute respiratory failure. The head helmet is a relatively novel interface that is as effective as the traditionally employed face-mask in delivering CPAP and can possibly be characterized as better for the patient's tolerance and, consequently, a longer duration of treatment. This review focuses on the main properties of the helmet and the issues related to its use, as shown by the physiological and bench studies. Clinical experience, both personal and reported in the literature, for the treatment of both cardiogenic and non-cardiogenic pulmonary edema is reviewed as well.

Risk factors for treatment failure in patients with severe acute cardiogenic pulmonary oedema.

Intubation is necessary in 7 to 20% of patients with severe acute cardiogenic pulmonary oedema despite optimal treatment. This study evaluated the usefulness of parameters largely available in clinical practice to predict the need for intubation in a population of acute cardiogenic pulmonary oedema patients treated with medical therapy and continuous positive airway pressure. The present retrospective cohort study involved 142 patients with severe acute cardiogenic pulmonary oedema who were admitted to coronary care or the intensive care unit of a university hospital and were treated by an in-hospital protocol. Physiological measurements and blood gas samples were evaluated at 'baseline' (just after admission), 'early' (one to three hours after beginning treatment) and 'late' (eight to 10 hours after beginning treatment). Twenty-two patients (15.5%) required intubation. A systolic blood pressure at admission lower than 140 mmHg was significantly associated with a higher risk for intubation, while hypercapnic patients or those with a reduced left ventricular ejection fraction at admission did not show a worse prognosis. A simple score based on largely available parameters (1 point for each: age >78 years, systolic blood pressure <140 mmHg at admission, arterial blood gas acidosis and heart rate >95 bpm at early time) is proposed. The rate of intubation according to this score ranged from 0% (score of 0) to 90% (score of 3). Our study found that simple parameters available in clinical practice are significantly associated with the need for intubation in acute cardiogenic pulmonary oedema patients treated with continuous positive airway pressure and medical therapy. A simple score to evaluate the need for endotracheal intubation is proposed.

[Two cases of de Morsier's olfactogenital syndrome]. / Illustrazione di due casi di sindrome olfatto-genitale di de Morsier.

Two cases of De Morsier's olfactogenital syndrome (complex hypogenitalism and anosmia) are presented. The first patient was of eunuchoid build and presented testicle and penile hypotrophy, depressed adrenal activity and gonad-stimulating pituitary function and distinctly below-normal urinary 17-ketosteroid values. The second subject was gynaecoid, menopausal gonadotrophic hormonal values, short urethra with no radiological signs of the prostate, and gynaecoid upper pelvic basin diameters. The karyotype pattern was normal XY in the first case and XX in the second. It is suggested that embryopathic or genetic changes, probably in the rhinencephalon, led to a direct pituitary nervous short-circuit that impeded normal FSH gonadal stimulation and hence gonadal influence on the phenotype throughout both intra- and extrauterine life, particularly at puberty.