Conclusions: It is recommended to reinforce the development of coping strategies which focus more on the problem than on the emotion, avoiding detrimental effects of emotional coping in blood pressure levels during pregnancy.Background: Hypertension is the most common medical condition during pregnancy. Hypertensive disorders are associated with an increased risk of adverse outcomes for both mother and fetus. This study examined the role played by personality and coping strategies in relation to blood pressure levels during pregnancy. The specific goal was to study whether coping strategies can mediate the effect of personality in pregnant women with hypertension. Methods: A sample of 351 pregnant women was enlisted, encompassing 192 pregnancies complicated by hypertension. This is a cross-sectional study where personality traits were measured by the five-factor model and coping was evaluated by Jalowiec’s coping inventory scale. Results: Personality can partially predict systolic and diastolic blood pressure. Openness to experience trait is inversely correlated with systolic and diastolic blood pressure. Conversely, emotion-focused coping directly correlated with blood pressure levels. Systolic (β = −0.14;  Hypertension is one of the most common causes of medical complications during pregnancy . It affeThere are different classifications for hypertensive disorders in pregnancy. According to the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy, they can be classified as follows: gestational hypertension, preeclampsia/eclampsia, chronic hypertension, and preeclampsia superimposed on chronic hypertension . GestatiImportantly, risk factors for hypertensive disorders in pregnancy may be of different etiologies. Nulliparity, maternal age, ethnicity, and higher blood pressures were identified as risk factors for developing hypertensive pregnancy disorders . Even asPersonality describes the consistent patterns of behavior, motivation, cognition, and emotion, which are unique for each person . The assRegarding previous research into personality issues, authors found that subjects who achieve high scores on neuroticism and low on openness to experiences have the worst cardiovascular response to stress reactions . AdditioIt is known that subjects who score higher on the neuroticism trait tend to feel more negative emotions, such as nervousness, tension, insecurity, and worry . ConsequCoping is defined as a set of cognitive and behavioral strategies that subjects put to use in order to manage their stress levels . InteresAdditionally, previous studies have already shown that coping might, instead, serve as a life quality mediator . A mediaUnderstanding human behavior is key to knowing how to approach health and disease issues in a singular and effective way. Although the literature is extensive on this topic, there are many questions that remain unclear concerning personality, coping, and blood pressure in the specific case of hypertension in pregnancy.We hypothesized that some traits of personality can be associated with increased blood pressure during pregnancy. Consistent with previous reports, it was found that openness to experience was able to predict blood pressure, and this effect was larger for systolic pressure . Since pThis cross-sectional study was conducted using an incidental sample made up of 351 pregnant women in the third trimester. Demographic and obstetric information were collected via medical records. Data included age, ethnicity, anthropometric data, education levels, employment and marital status, social support, parity, and previous pregnancy outcomes. Clinical features, such as laboratory tests , history of anemia, hypertension, or any other physical or psychological complication, were extracted from the medical records.This instrument measures global cognitive functioning, such as temporal evaluations, space, attention, calculations, memory, language, and visual constructive capacity . In thisIt consists of 44 self-report items constructed to allow quick and efficient assessment of the 5 personality dimensions . The insThe Jalowiec’s Coping Inventory  was adapThis study comprises the Line of Research on Hypertension in Pregnancy. This work partly consists of a broader research effort, with previous results published but with different investigation objectives ,30. ThusAfter descriptive and relational analyses based on Person’s correlation coefficient, a regression analysis was carried out to analyze the mediating role of coping. The statistical analysis was performed using SPSS 23 (IBM), and the mediational analysis used PROCESS macro . This meA total sample of 351 women participated in the study. According to prior hypertension in pregnancy diagnosis, women were classified as follows: (i) gestational hypertension (16.8%), (ii) preeclampsia syndrome (29.3%), (iii) chronic hypertension (8.5%), and (iv) control group encompassing healthy women with uncomplicated pregnancies (45.3%). With regards to the educational level, 60.7% had basic studies, 33.6% intermediate, and 5.7% superior ones. The proportion of Caucasian women in the control group was 24% and in the hypertensive group was 22%. The mean gestational age in the control group was 271.76 (SD = 12.77) days and in the hypertensive group 264.75 (SD = 19.52) days. In total, 32% of the control group were primiparous and 40% of women with hypertension were pregnant for the first time. The proportions of women that work or study in the control and hypertensive groups were 76% and 82%, respectively. Regarding social support, 0.9% of the control group and 1.3% of hypertensive women reported that they have no one to count on. Finally, more than 77.5% reported being married or in a relationship. Other demographic data are depicted in Secondly, the relationship between variables under study was examined. The Pearson coefficient was calculated among systolic and diastolic pressure, along with the Big Five traits of personality and coping (problem- and emotion-focused). Note that openness to experience trait and emotion-focused coping correlated with both blood pressures .p < 0.05) and the group : F  = 13.35; p < 0.001; R2 = 0.30. Systolic blood pressure was also predicted by openness to experience , anxiety , and the group : F  = 23.97; p < 0.001; R2 = 0.42.On the other hand, a regression analysis on the prediction of blood pressure was carried out. Independent variables included the group (control and hypertensive) and the Big Five traits of personality and coping .A mediational approach was carried out. The model was estimated in both strategies of coping simultaneously. In this way, the whole dataset was employed in order to have more data variability in the dependent variable blood pressure . As expected, prediction of diastolic and systolic pressure, though openness to experience, reached the statistical significance level with a similar explained variance . Conscientiousness just predicted the Systolic pressure .A similar pattern occurred for agreeableness for both pressures (In this study, we found that personality can partially predict systolic and diastolic blood pressure. Contrary to expectation, no effects were observed for neuroticism, when considered as a mediator of association between personality and blood pressure during pregnancy.Neuroticism is known as a negative personality trait, understood as a tendency to feel anxiety, guilt, sadness, anger, and nervousness . MoreoveOur data shows that the openness to experience trait is inversely correlated with systolic and diastolic blood pressure. On the other hand, emotion-focused coping directly correlated with blood pressure levels. Regarding personality, previous studies have also found similar results. Authors found that personality, especially openness, could moderate the association between stressful events and blood pressure . Other sAs highlighted by other authors, openness to experience has a positive correlation with cognitive ability and adaptive behaviors . These aIndeed, conscientiousness-related traits, including aspects related to duty, planning, and organization , were noAdditionally, extraversion and agreeableness traits show no effects as mediators of associations between personality and blood pressure in pregnancy. Extraversion is related to enthusiasm, interest, and expansiveness characteristics, whereas agreeableness is linked to altruism and kindness . DespiteOn the other hand, we found that those participants in the study who had coping focused on emotion also had higher average blood pressure levels. The emotion-focused coping strategy is understood as passive coping or avoidance, which is effective as a short-term coping strategy . NeverthOur data shows that women who had problem-focused coping strategies did not present better blood pressure levels than others. However, we found that problem-focused coping has a mediating effect instead of a predictive role. Problem-focused coping strategies are associated with efforts to modify or resolve the stressor and usually help people to experience low emotional stress levels , which cOn the other hand, these findings are of interest because it is suggested that women can develop more appropriate coping strategies when facing difficult situations, under some circumstances. In other words, our results point out that achieving higher scores in problem-focused coping strategies in comparison to emotion-focused coping during pregnancy did not influence systolic or diastolic blood pressures. This is a desirable strategy, however, as emotional coping has detrimental effects on blood pressure.The present study has some limitations. First and foremost, it is an incidental sample and not a random one. Nevertheless, we have a big sample that minimizes selection bias. Data were cross-sectional so the causality among the variables could not be inferred. Moreover, our data excluded women with other comorbidities, such as a previous diagnosis of kidney disease, a history of diabetes, and fetal malformation. These women may present different coping strategies; therefore, studies focused on a better understanding of this situation may be of clinical relevance. Future studies should focus on more complex models and other variables could be included in analysis.The computation of the present data establishes that both the openness to experience trait and emotion-focused coping are correlated with systolic and diastolic blood pressure. Detrimental effects on blood pressure were found for emotional coping. Furthermore, problem-focused coping strategies have a mediation effect in personality traits, instead of a predictive role.Considering the results of the current study, on a theoretical level, it was possible to implement the classic models to better understand the pregnant population, more specifically, women with hypertension. On a practical level, it is very interesting to know that we can improve coping strategies that can mediate the personality effects on blood pressure during pregnancy. Moreover, this not only favors physical health for women and their fetuses, but also their well-being and quality of life.


Postoperative pulmonary complications and cardiovascular complications are major causes of morbidity, mortality, and resource utilization in cardiac surgery patients.To investigate the effects of airway pressure release ventilation (APRV) on respiration and hemodynamics in post cardiac surgery patients.A single-center randomized control trial was performed. In total, 138 patients undergoing cardiopulmonary bypass were prospectively screened. Ultimately 39 patients met the inclusion criteria and were randomized into two groups: 19 patients were managed with pressure control ventilation (PCV) and 20 patients were managed with APRV. Respiratory mechanics after 4 h, hemodynamics within the first day, and Chest radiograph score (CRS) and blood gasses within the first three days were recorded and compared.–1⋅m2; p < 0.05), and shock volume index  were also observed in the APRV group after 4 h as well as within the first day (p < 0.05). Compared to the PCV group, the PaO2/FiO2 was significantly higher after 4 h in patients of APRV group  and within the first three days (p < 0.05) in the APRV group. CRS revealed less overall lung injury in the APRV group (p < 0.001). The duration of mechanical ventilation and ICU length of stay were not significantly .A higher cardiac index (3.1 ± 0.7 vs. 2.8 ± 0.8 L⋅minCompared to PCV, APRV may be associated with increased cardiac output improved oxygenation, and decreased lung injury in postoperative cardiac surgery patients. Postoperative pulmonary complications and cardiovascular complications are major causes of morbidity, mortality and resource utilization in cardiac surgery patients . PatientAirway pressure release ventilation (APRV) mode is a lung protective strategy that has been proposed to treat refractory hypoxemic respiratory failure while preventing ventilator-induced lung injury . APRV waThis study protocol was approved by the Medical Ethics Committee of Sir Run Run Shaw Hospital and Zhejiang University School of Medicine (20181225-6). Written informed consent was obtained from all patients or their legal representatives prior to the study. The clinical trial number was ISRCTN92666776.Consecutive patients scheduled for cardiac surgery and afterward referred to the intensive care unit (ICU) from March 1st to May 31st, 2020 were included in the study. The exclusion criteria were age less than 18 years, history of chronic obstructive pulmonary disease, or asthma, mechanical ventilation prior to the operation, use of a mechanical device to maintain hemodynamics prior to the operation and extubation within 30 min after surgery . All pat2O and fraction of inspired oxygen (FiO2) of 50%. Subsequently, the anesthesia was maintained with a continuous infusion of fentanyl and propofol, and rocuronium was used as a paralytic. The CPB was established via a standard median sternotomy, aortic root cannulation, and single or double atrial cannulation for venous return. CPB flow was kept between 2.2 and 2.5 l/min/m2 with a target mean perfusion pressure of 60 mmHg. If necessary, norepinephrine was administered to reach the targeted blood pressure. Weaning from CPB was initiated once the patient’s cardiac rhythm had stabilized and normothermia had been achieved. Standard clinical postoperative care with goal-directed therapy was initiated after separating the patient from the CPB machine and was continued during the ICU stay to maintain hemodynamic stability. The central venous pressure (CVP) was kept between 10 and 12 mmHg and pulmonary artery wedge pressure (PAWP) between 15 and 18 mmHg by the administration of intravenous fluids. Inotropic support with epinephrine was initiated in order to maintain a cardiac index (CI) greater than 2.2 l/min/m2. Milrinone was administered if epinephrine was increased to a maximum of 0.1 μg/kg/min and additional inotropy was needed. The target mean arterial blood pressure was set at >65 mmHg and norepinephrine was administered if necessary. Lactate was targeted at <2 mmol/L and mixed venous oxygen saturation (SvO2) at >70%. An intra-aortic balloon pump was inserted if further support was required. Hemoglobin was maintained at >70 g/L with transfusion of packed red blood cells. The decision to weaning patients from inotropic and vasopressor medications was made by the attending ICU physicians based on the assessment of hemodynamic data, urine output and physical status. These physicians were blinded in our study. Pain medication was used in all patients to maintain a pain scale score less than three points, as measured by a numerical rating scale or the Critical Care Pain Observational Tool  with the following settings: a tidal volume of 8 ml/kg, respiratory rate of 12 breaths per min, positive end-expiratory pressure (PEEP) of 5 cmHnal Tool . Patient2O); the Pplat measured during conventional ventilation by using the ventilator’s inspiratory pause control. The levels of PEEP and FiO2 were based on the patient’s underlying clinical condition to obtain an SpO2 of 90%–95% or an arterial partial pressure of O2 (PaO2) of 60–80 mmHg. The respiratory rate was set to maintain a partial pressure of arterial carbon dioxide (PaCO2) between 35 and 45 mmHg. A stepwise maximum alveolar recruitment maneuver (RM) was performed in all patients.After admission to the ICU, patients were connected to Evita 4 ventilators . All patients were ventilated with volume-controlled ventilation in assist control mode for the first 30 min. The tidal volume was set to 6–8 ml/kg per kilogram of predicted body weight according to the plateau pressure (Pplat)  was set to 3.6–6.0 s . The duration of the release phase (TLow) was set to terminate at 75% of the peak expiratory flow rate. This parameter was calculated and monitored for adjustment based on the angle of deceleration noted on the expiratory flow waveform. The PHigh, THigh, TLow and FiO2 were titrated based on interpretation of the expiratory flow waveform and arterial blood gasses , CVP, mean pulmonary artery pressure (PAP), and PAWP, end diastolic velocity (EDV), pulmonary vascular resistance index (PVRI), cardiac output (CO), CI, and stroke volume (SV) were measured  and recorded . The Swan-Ganz catheter was removed after the first ICU day after hemodynamics stability was confirmed.The baseline respiratory mechanics were recorded at once the patients admitted to ICU and connected to the ventilator (T0), 1 h after mechanical ventilation (T1), and 4 h after mechanical ventilation (T2). Dynamic lung mechanics were calculated by the ventilators. PEEPi measurement was performed with end-expiratory occlusion. The Pplat was measured with a breath holding technique at the end of inspiration when the patients were sedated maintained Richmond at a Agitation Sedation Scale (Rass) score of −2. The mean airway pressure was calculated by the ventilator as the geometric mean of the pressure-time curve. Arterial blood gasses were examined every 4 h on the first day and once every morning on days 2–3 . The central laboratory of Sir Run Run Shaw Hospital performed clinical pathology tests and blood cultures.Chest radiograph score (CRS)  were obtThe primary endpoints of the study were the effects of APRV on cardiorespiratory function, including lung mechanics, blood gasses and CRS within 3 days, and hemodynamic parameters within 1 day. The secondary endpoint was the duration of mechanical ventilation and ICU stay.W-test. The results were expressed as the means ± standard deviations. For blood gasses and hemodynamics, data were analyzed by two-way analysis of variance (ANOVA), with the ventilation mode and time after randomization as independent variables. Differences between the means were analyzed separately with a post hoc Newman–Keuls multiple comparison test. Baseline demographics and respiratory mechanics of the two groups were compared using two-tailed unpaired Student’s t-tests or chi-squared tests, where applicable. Differences were considered statistically significant for results with p < 0.05.Data were tested for normal distribution with the Shapiro–Wilks In total, 134 patients were screened in the present study. Ninety-five patients were enrolled, and ultimately 39 patients were randomized . The typp = 0.017 and p = 0.024, respectively). PVRI and right ventricular work (RVSW) were lower in the APRV group .The APRV and PCV groups demonstrated hemodynamic stability during mechanical ventilation. MAP, MPAP, and CVP changes did not differ between groups at any measurement time points . The incp = 0.000) and Pplat  after randomization. The Pmean was significantly higher in the APRV group than in the PCV group after transition from assist-control ventilation (p = 0.000)  were extubated before 8 h. The compliance and resistance were calculated by the ventilator with using least squares Regression. The ID of the endotracheal tube was 8.0 mm for males and 7.5 mm for females. There was no significant difference between the PCV and APRV groups in lung compliance and airway resistance or other baseline pulmonary characteristics. Patients in the PCV group had a higher peak airway pressure  . Cst aft2/FiO2 (p = 0.002) and central venous oxygen saturation  were found in the APRV group compared to the PCV group after 4 h. Arterial pH, PaCO2, and SaO2 were comparable in the two groups (p = 0.000). CRS was improved in the APRV group compared to the PCV group . The ICU length of stay was not significantly different   .2/FiO2 and ScvO2, increased CI and improved CRS. This study is the first randomized trial demonstrating the potential benefit of APRV in patients after cardiac surgery.Airway pressure release ventilation made effects of lung mechanics, hemodynamics and blood gasses in post cardiac surgery patients. Compared with PCV, we found that APRV may be associated with higher Cst, PaORight ventricular (RV) failure post cardiac surgery increases morbidity and mortality . Lung cop < 0.05). APRV may ameliorate lung collapse, increases lung volume and decreases PVR.Classic physiology states that PVR has a U-shaped relationship with lung volume, its lowest value corresponding to functional residual capacity. According to Shekerdemian , PVR, th2O have minimal effects on CO, primarily because during the inspiratory phase, the abdominal compartment is pressurized causing compression of the liver and the lungs. Thus, with normal blood volume, increased intrathoracic pressure in a certain range does not lead to a significant decrease in blood pressure. In our research, standard clinical postoperative care with goal-directed therapy was used to maintain hemodynamic stability. Therefore, despite the higher mean airway pressure in the APRV group, the MAP and MPAP were similar to those in the PCV group. The CI was higher in the APRV group , was different . APRV maChest radiograph score assesses the extent of pulmonary exudative lesions by bilateral lung infiltration images. Our study found CRS was lower in the APRV group compared to PCV group, suggesting that the range of exudative lesions is smaller.a priori sample size calculation for future multi-centered randomized control trials.Limitations of our study include the fact that the number of patients enrolled was not large enough for stratification analysis. The baseline difference in the lactate level could have been caused by the small sample size. Our current data did not suggest the application of APRV would have significantly reduced the MV and ICU length of stay. Limited sample size in the present study could be one of the reasons for this finding. Urine output was not recorded after cardiac surgery. Although urine output is a non-invasive, primary variable for understanding the CO, it is often insufficient for hemodynamic evaluation, rapid assessment, and the identification of occult or compensated shock . The durIn conclusion, compared to PCV, APRV may be associated with increased CO, improved oxygenation, and decreased lung injury after post operation of cardiac surgery.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the Ethics Committee of Sir Run Run Shaw hospital. The patients/participants provided their written informed consent to participate in this study.HG and KY designed the study. HG and LL drafted the manuscript with input from all authors. YX, PX, and KD were responsible for collecting clinical data. QP analyzed the data with input from all authors. All authors contributed to the interpretation of the data and approved the final of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Idiopathic normal pressure hydrocephalus (iNPH) and late-onset idiopathic aqueductal stenosis (LIAS) are two forms of chronic adult hydrocephalus of different aetiology. We analysed overnight intracranial pressure (ICP) monitoring to elucidate ICP waveform changes characteristic for iNPH and LIAS to better understand pathophysiological processes of both diseases.98 patients with iNPH and 14 patients with LIAS from two neurosurgical centres were included. All patients underwent diagnostic overnight computerised ICP monitoring with calculation of mean ICP, ICP heartbeat related pulse wave amplitude calculated in the frequency domain (AMP) and the time domain (MWA), index of cerebrospinal compensatory reserve (RAP) and power of slow vasogenic waves (SLOW).ICP was higher in LIAS than iNPH patients . AMP and MWA were higher in iNPH versus LIAS . RAP and SLOW indicated impaired reserve capacity and compliance in both diseases, but did not differ between groups. INPH patients were older than LIAS patients .ICP is higher in LIAS than in iNPH patients, likely due to the chronically obstructed CSF flow through the aqueduct, but still in a range considered normal. Interestingly, AMP/MWA was higher in iNPH patients, suggesting a possible role of high ICP pulse pressure amplitudes in iNPH pathophysiology. Cerebrospinal reserve capacity and intracranial compliance is impaired in both groups and the pressure-volume relationship might be shifted towards lower ICP values in iNPH. The physiological influence of age on ICP and AMP/MWA requires further research. Idiopathic normal pressure hydrocephalus (iNPH) is part of the large group of neurodegenerative diseases affecting the aging population. It is characterised by a clinical triad of progressive gait impairment, decline in cognitive function and incontinence. The natural history of iNPH is generally unfavourable with worsening neurological symptoms and reduced survival , 2. TreaThe pathophysiological processes of iNPH remain incompletely understood, resulting in a lack of clear diagnostic criteria. This makes selection of patients for surgical treatment and differentiation from other neurodegenerative diseases a challenge. Current evidence indicates that iNPH is thus underdiagnosed and undertreated . It is nLate-onset idiopathic aqueductal stenosis of the adult (LIAS) is a less common form of chronic adult hydrocephalus . The undThe aim of this study was to investigate differences between the physiologic ICP waveform characteristics of patients with iNPH and LIAS. Despite the similar clinical features of these two forms of chronic adult hydrocephalus, we hypothesised that the relatively well-defined entity of LIAS would present with a distinct pattern of ICP features attributable to the impaired aqueductal CSF flow. Differentiation of the LIAS ICP-profile from the ICP-profile of iNPH might help to elucidate ICP characteristics for iNPH and LIAS and thus provide insight into pathophysiological processes of both diseases.We included patients treated at the Department of Neurosurgery, Wollongong Hospital, Illawarra Shoalhaven Local Health District, NSW, Australia between 2013–2020 and the Department of Neurosurgery, Eberhard Karls University Hospital, Tübingen, Germany, between 2009–2018 under the care of the two senior authors. Included patients underwent diagnostic intracranial pressure monitoring for investigation of iNPH or LIAS and were retrospectively identified from the ICP monitoring databases at both institutions. Clinical records, MRI and CT scans of the brain were reviewed for all patients.The patient selection process and inclusion procedure is described in detail in Fig. LIAS patients had chronic symptoms as described by Fukuhara et al. with more than 6 months duration . They haWe only included patients with neurological improvement after CSF diversion in the final analysis. This is because we see improvement post shunting as the diagnostic gold standard and confirmation that patients suffered from symptomatic hydrocephalus and not other neurological disease. The disease severity of the iNPH patients was assigned retrospectively after review of the patients’ clinical notes using the Oslo-iNPH grading scale . This siPatients underwent diagnostic ICP monitoring for evaluation of chronic hydrocephalus as part of routine management. An ICP transducer was inserted through a right frontal burr hole. At Wollongong Hospital a Codman microsensor ICP transducer  was used, in Tübingen a Neurovent P sensor . ICP monitoring was performed on a neurosurgical ward for 1–3 nights. The ICP raw data signal was digitally sampled using ICM + software  . During The ICP raw data was analysed using ICM + software version 8.3 for the following mean parameters from the 10-hour overnight monitoring:The mean ICP was calculated.The ICP pulse pressure amplitude (AMP): AMP was calculated from the amplitude of the fundamental harmonic in the frequency range of 30–140 beats per min (bpm) over 10 s intervals and averaged every 60 s.Index of cerebrospinal compensatory reserve capacity (RAP): This is a marker of cerebrospinal compensatory reserve capacity and indirectly of compliance , 11. It Heart rate (HR): HR was calculated from the frequency of the fundamental harmonic in the frequency range of 30–140 bpm over 10 s intervals and averaged every 60 s.The ICP amplitude of the respiration induced waves (RESP): RESP was calculated from the amplitude of the fundamental harmonic in the frequency range of 7–30 bpm over a 120 s time window and updated every 60 s.Respiratory rate (RR): RR was calculated from the frequency of the fundamental harmonic in the frequency range of 7–30 bpm over a 120 s time window and updated every 60 s.The amplitude of the slow vasogenic waves of the ICP signal (SLOW): SLOW was calculated from the square root of the power in the frequency range of 0.3–3 bpm over a 10 min time window updated every 60 s .The ICP raw data was also analysed in the time domain using Sensometrics software  . The folThe ICP mean pulse pressure wave amplitude in the time domain (MWA): The software algorithm identifies the amplitude of each single heartbeat induced pressure wave in the continuous ICP signal (the difference between diastolic minimum and systolic maximum pressure). MWA is calculated as the mean ICP pulse pressure wave amplitude for consecutive 6 s time windows. The software algorithm also identifies artefacts and time windows containing less than four valid heartbeat induced ICP waves are excluded.Rise time of the ICP pulse pressure wave (RT): The RT was calculated as the time from the diastolic minimum to the systolic maximum for each heartbeat related ICP wave for consecutive 6 s time windows.Rise time coefficient of the ICP pulse pressure wave (RTc): The RTc was calculated as the ratio of the amplitude over the rise time of each heartbeat induced ICP wave for consecutive 6 s time windows.Prism software  was used for statistical analysis. We used the Mann-Whitney-U test and chi-square test for comparison of variables between groups. Multiple linear regression models were used to analyse for potential confounders on the dependent variables. Correlation between selected parameters was calculated using non-parametric Spearman correlation coefficient. The probability of a type-1 error (α) of 5 % was accepted as being statistically significant.98 patients with iNPH showing improvement after VP-shunt insertion were included in this study. The median preoperative Oslo-score was 11 (range 4–14) and the median postoperative Oslo-score was 13 (range 7–15). They showed a median of 2 points (range 1–8) of improvement after shunt surgery. 14 patients with LIAS showing neurological improvement after VP-Shunt (n = 9) or ETV (n = 5) were included. 10 patients had improvement in gait, 8 in cognitive function, 7 in incontinence, and 7 reported better headache control. 11 patients had improvement in more than one domain. LIAS patients were younger and had a higher Evans index. Demographic and radiological data is summarised in Table Figure Table We found a significant correlation between ICP pulse wave amplitude calculated in the frequency domain (AMP) and time domain (MWA) of r = 0.93, p < 0.001.2 = 0.15). In another multiple linear regression model age had no confounding effect on AMP . Both models were significant, but had a low adjusted R2.In a multiple linear regression model age had a confounding effect on ICP between disease groups (iNPH versus LIAS) . RR was higher in Tübingen than in Wollongong . AMP did not differ between centres in iNPH patients . MWA was also not different between centres in iNPH . Other clinical and monitoring parameters did not differ between centres in iNPH patients.In LIAS patients the Evans index was lower in the Tübingen cohort . From the ICP derived parameters the following showed statistically different values between Tübingen and Wollongong, respectively: RR, 13.0 ± 1.1 bpm versus 15.1 ± 2.0 bpm, p = 0.04; RESP, 0.34 ± 0.07 mmHg versus 0.84 ± 0.68 mmHg, p = 0.012; and RTc, 19.7 ± 5.0 mmHg/s versus 31.9 ± 12.7 mmHg/s, p = 0.019). Other clinical and monitoring parameters did not differ between centres in LIAS patients.This study investigated differences between the ICP profile of patients with iNPH and LIAS obtained from overnight recordings. We found mean ICP to be almost twice as high in LIAS patients compared to iNPH; however, mean ICP in LIAS was still in a range of ≤ 15 mmHg, generally considered normal. This is consistent with the idea that despite the often complex CSF pressure versus flow relationship in hydrocephalus the chronic compensated nature of the aqueductal flow impairment and supratentorial CSF accumulation causes a non-critical elevation of ICP and explains higher values compared to an iNPH cohort where aqueductal CSF flow is not obstructed and free communication between inner and outer CSF spaces can be assumed.Interestingly, iNPH patients showed a significant elevation in AMP and MWA as compared to LIAS, despite the fact that they had a lower ICP. This is a most important finding, since with a given exponential pressure-volume relationship higher ICP are to be associated with higher AMP/MWA, and not vice versa. The increased AMP/MWA in iNPH at lower ICP indicates a very different pressure-volume relationship with the typical pressure-volume curve shifted to the left and a possibly narrower and steeper curve. This way the small intracranial volume changes caused by the cardiac pulsations induce larger ICP wave amplitudes at lower pressures.Cerebrospinal reserve capacity and compliance measured with RAP were equally compromised in both groups, despite the higher average ICP values in LIAS. This again suggests a shift of the pressure-volume curve towards lower ICP values in iNPH, so that despite lower ICP a similar relationship between fluctuations in ICP and AMP results.out) derived from the lumbar compartment during lumbar infusion studies in NPH patients with open or stenotic cerebral aqueducts [out was higher in patients with an open aqueduct. This is again interesting as it indicates that the pressure differences between iNPH and LIAS patients obtained from the lumbar and cranial compartments might differ and should not be considered interchangeable.A previous investigation by González-Martínez et al. looked at differences between cerebrospinal fluid pressures, AMP and resistance to CSF outflow  might have introduced further bias and should ideally be avoided in future prospective investigations.ICP is non-critically elevated in LIAS and lower in iNPH. AMP/MWA as a marker of intracranial heartbeat related pulsations is elevated in iNPH. The origin of these increased pulsations necessitates further research to understand this possible mechanism of iNPH better. In both disease groups intracranial reserve capacity is impaired with a possible shift of the pressure-volume curve towards lower ICP values in iNPH. The physiological influence of age on ICP and derived parameters requires additional investigations.


Hemodynamic monitoring is an essential component in the care for critically ill patients. A range of tools are available and new approaches have been developed. This review summarizes their availability, affordability and feasibility for hospital settings in resource-limited settings.Evidence for the performance of specific hemodynamic monitoring tools or strategies in low-income and middle-income countries (LMICs) is limited. Repeated physical examination and basic observations remain a cornerstone for patient monitoring and have a high sensitivity for detecting organ hypoperfusion, but with a low specificity. Additional feasible approaches for hemodynamic monitoring in LMICs include: for tissue perfusion monitoring: urine output, skin mottling score, capillary refill time, skin temperature gradients, and blood lactate measurements; for cardiovascular monitoring: echocardiography and noninvasive or minimally invasive cardiac output measurements; and for fluid status monitoring: inferior vena cava distensibility index, mini-fluid challenge test, passive leg raising test, end-expiratory occlusion test and lung ultrasound. Tools with currently limited applicability in LMICs include microcirculatory monitoring devices and pulmonary artery catheterization, because of costs and limited added value. Especially ultrasound is a promising and affordable monitoring device for LMICs, and is increasingly available.A set of basic tools and approaches is available for adequate hemodynamic monitoring in resource-limited settings. Future research should focus on the development and trialing of robust and context-appropriate monitoring technologies. The level of patient monitoring and organ support feasible in the care for patients with critical illness differs substantially around the globe, and is mainly driven by availability and affordability of the different tools. Hemodynamic monitoring is an essential part of critical care as many patients in the ICU experience hemodynamic instability for a large variety of reasons. Shock is defined as insufficient perfusion at the tissue level, and the ultimate hemodynamic parameter to monitor is perfusion of the microcirculation of vital organs. Yet, quantifying microcirculatory flow is challenging. Clinical assessment of for instance nail bed or skin perfusion or acute changes in organ function of the brain, kidney or other organs, provide an indication for the adequacy of tissue perfusion. There are techniques to quantify local tissue perfusion, and some laboratory parameters, such as blood lactate, provide a rough estimate for overall tissue perfusion.In clinical practice, however, we rely mainly on monitoring macrocirculatory parameters including cardiac function, intravascular filling status, blood pressure and, derived from these, vascular resistance. These will guide clinical management, including fluid therapy, vasopressor and inotropic drugs, and other interventions aiming to optimize cardiac output, yet avoiding fluid overload causing tissue and pulmonary edema. Hemodynamic monitoring of the macrocirculation include simple clinical assessments, non-invasive and invasive monitoring tools.▪▪].The optimal approach and choice of devices and approaches are different in settings with limited resources, and will be guided by costs, complexity of maintenance, human and material infrastructure, safety, and other factors. We evaluated the value of clinical parameters and monitoring devices in LMICs, based on criteria of availability, affordability, and feasibility ▪▪.A literature search was performed using the Medline OVID, EMBASE Cochrane, and PubMed databases. Our search was restricted to studies in adult patients but not to specific years of publication, although with an emphasis on manuscripts published over the last 5 years. The following search terms were used: ‘cardiovascular monitoring’ OR ‘hemodynamic monitoring’ OR ‘invasive’ OR ‘non-invasive’ OR ‘device’ OR ‘critical illness’ OR ‘critically ill’ OR ‘LMICs’. Furthermore, subject terms were also combined with terms referring to specific monitoring techniques, such as ‘ultrasound’ OR ‘echocardiogram’. Reference lists of identified manuscripts were hand-searched to identify further relevant publications.Simple clinical assessments can provide crucial information on the adequateness of the microcirculation of vital organs, and other tissues. Acute changes in consciousness, anxiety, confusion, or delirium can all be a sign of decreased brain perfusion. Oligo or anuria can be a sign of decreased renal perfusion. Deep breathing or tachypnea can be the respiratory compensation for a lactic acidosis that may originate from anaerobic glycolysis because of inadequate tissue perfusion. Bowel dysfunction can be caused by decreased gut perfusion. Cold extremities, including the tip of the nose, fingers, legs, and toes, as well as mottling of the skin can denote shock. In general, the specificity of these clinical parameters is limited, as these can all have alternative causes. However, their assessments do not require resources apart from skilled medical staff, and it is important to monitor these parameters in the critically ill patients frequently. Some of these parameters are reviewed more systematically below.In general, an adequate urine output of more than 0.3--0.5 ml/kg/h  is consiSkin mottling reflects microcirculatory alterations in the skin . Patchy Targeting a capillary refill time 3 s or less was shown as an adequate endpoint for fluid resuscitation . One mulSkin temperature gradients, defined as the difference in skin temperature between an extremity and a more proximal skin zone, for example, between the fingertip and forearm, or between the toe and central core , can be Monitoring blood lactate can help identify patients at risk for adverse outcomes in the emergency department in LMICs ▪. AdditiMicrocirculatory monitoring techniques enable direct visualization of capillary blood flow with a microscopic camera, which can be placed on the sublingual or rectal capillary beds. Specific software has been developed to quantify capillary perfusion. Although some groups have advocated the use of sublingual capillary perfusion assessed by these devices as a cardiovascular resuscitation endpoint , this haFrequent basic physical examination using simple and cheap tools provide crucial information on the hemodynamic status of the critically ill patient. This includes automated blood pressure measurements, basic three-lead electrocardiography to monitor heart rate and rhythm, and monitoring of the pulse contour. A mean arterial blood pressure (MAP) of at least 65 mmHg is usually considered adequate. However, in the individual patient, tissue perfusion can be highly inadequate despite an appropriate blood pressure, for instance because of severe vasoconstriction. Conversely, some patients tolerate a low blood pressure very well, without any sign of tissue hypoperfusion, including the brain. Thus, interpretation of the blood pressure values always needs to be personalized.The pulse pressure is the difference between the SBP and DBP. In patients with severe dengue, characterized by a generalized capillary leak, the pulse pressure is recommended for guiding fluid therapy . A narroA weakening of the pulse during inspiration of more than 10 mmHg in SBP is called a pulsus paradoxus and can be caused by a cardiac tamponade, constrictive or restrictive pericarditis, or severe bronchial asthma.Echocardiography is increasingly available in LMICs, and offers direct bedside assessments of stroke volume (SV), cardiac output, and valvular disease. Unlike echocardiography, traditional cardiac output assessments using intravascular catheters and dilution techniques are inaccurate in the presence of right heart failure, several valvular lesions, and arrhythmias. Echocardiography is easy to integrate with other point-of-care ultrasound techniques, such as lung or abdominal ultrasound, and is also useful for differentiating types of shock ▪. HoweveThe left ventricle is assessed by echocardiography for end-diastolic diameter, shape, and gross abnormalities of contractility. The right ventricle is assessed for size and shape relative to the left ventricle, position of the interventricular septum, and free wall longitudinal contractility . In the Noninvasive or minimally invasive methods to estimate cardiac output use noninvasive devices with specific algorithms, for example, noninvasive pulse contour analysis, thoracic bioreactance, Doppler ultrasound cardiac output monitoring, or minimally invasive pulse contour analysis, which require a peripheral arterial line. However, the accuracy of noninvasive cardiac output estimation is generally inferior to methods using thermodilution , requireMonitoring through invasive catheters, including central venous catheters, pulmonary artery catheters, and arterial catheterization for invasive techniques including Fick's method or thermodilution have limited applicability in resource-limited settings, because of complexity of the procedure, costs, and other factors. Moreover, independent of the setting, the use of pulmonary artery catheters was shown to have no effect on important outcomes in intensive care patients .Clinical assessment of the jugular venous pressure is an insensitive measure of intravascular volume status, as well as fluid responsiveness . Lung auA central venous jugular or subclavian line is part of standard care in most ICUs, also in LMICs. This allows for quick assessment of the central venous pressure (CVP) representing the filling pressure of the right side of the heart, which can be used as a measure of the intravascular filling status. However, a systematic review showed a poor correlation between the CVP and the response to fluids .Fluid responsiveness is defined as the ability of the heart to increase the cardiac output in response to volume expansion. Fluid responsiveness indicates the patient position on the Starling ventricular function curve, and can thus identify patients that are ‘over the top’ of the Starling curve who will not benefit from fluid loading. Although dynamic transthoracic echocardiogram measures are one of the reference standards for assessing fluid responsiveness in LMICs , there aTransthoracic echocardiography can be used to estimate the left ventricle filling pressure, which can guide fluid management ▪. Systol2O or less, the inferior vena cava distensibility index, defined as (maximum inferior vena cava − minimum inferior vena cava)/minimum inferior vena cava × 100 (%) [2O, the inferior vena cava distensibility index is inaccurate for predicting fluid responsiveness [In invasively ventilated patients receiving tidal volumes at least 8 ml/kg predicted body weight and positive end-expiratory pressure (PEEP) 5 cmH 100 (%) , is an asiveness . Also insiveness .Mini-fluid challenge test can help predict fluid responsiveness in patient receiving invasive ventilation . TransthThe passive leg raising test is a feasible and affordable tool to guide fluid resuscitation in patients with or without invasive mechanical ventilation, including in resource-limited settings . It is cIn patients receiving invasive ventilation, the intrathoracic pressure increases during the inspiratory phase resulting in a decrease of venous return. In the end-expiratory occlusion test, the increase in intra-thoracic pressure is temporarily prevented, causing an increase in venous return, cardiac preload, and SV in preload-responsive patients. Therefore, an increase in cardiac index during the end-expiratory occlusion test can predict the fluid responsiveness . In ordeExtravascular lung water is a key variable in fluid resuscitation. Ultrasound provides an easy and reliable method to estimate extravascular lung water. An increase of extravascular lung water creates so called B-lines, which are comet-like signals generated from hyperechoic subpleural interstitial edema ▪. The noEstimation of extravascular lung water through transpulmonary thermodilution devices, like the Pulse index Continuous Cardiac Output, is in general less suitable for ICU settings in LMICs as these require expensive invasive catheters, pressure transducers, and monitoring devices .Approaches and tools for hemodynamic monitoring in LMICs will have to be operated often in settings with challenging environmental conditions, a complex supply chain, inadequate operator training, and limited resources for purchasing and maintaining equipment. At the same time, the approaches and tools will need to have comparable performance and reliability as those for use in resource-rich settings. Hemodynamic monitoring that uses invasive, complicated procedures or expensive devices will often not be available, affordable or feasible in LMICs. Ultrasonography skills for hemodynamic monitoring using low-cost, portable ultrasound devices can be easily acquired by a variety of medical personnel, and monitoring by ultrasound techniques is recommended for ICUs in LMICs. Setting-appropriate cardiovascular monitoring approaches are summarized in Fig. We thank Professor Kunchit Piyavechviratana for his support and advice.Professor Arjen M. Dondorp is supported by the Wellcome Trust of Great Britain (220211/Z/20/Z).There are no conflicts of interest.


Patients with severe acute pancreatitis (SAP) have gastrointestinal dysfunction, and enteral nutrition intolerance is easy to occur during the implementation of enteral nutrition, which leads to the suspension or termination of enteral nutrition. Enteral nutrition cannot tolerate the influence of many factors. At present, there is a lack of analysis on the influencing factors of enteral nutrition intolerance in patients with SAP. Therefore, this study analyzed the factors of enteral nutrition intolerance in patients with SAP by meta-analysis, to provide a basis for the protection of enteral nutrition in patients with SAP.Databases  were searched using index words to find relevant studies published before March 2021. Meta-analyses of relative risk were performed for the identification of risk factors.We will disseminate the findings of this systematic review and meta-analysis via publications in peer-reviewed journals.This study systematically reviewed the existing evidence and determined the incidence and predictors of enteral nutrition intolerance in patients with SAP. However, with the application of parenteral nutrition, the adverse reactions after treatment are becoming more and more prominent. It was found that with the gradual extension of parenteral nutrition time, the damage of gastrointestinal function and adverse reactions gradually increased, and even induced multiple organ function damage.Severe acute pancreatitis (SAP) is a common clinical critical disease with rapid progress and high mortality.,9 The clinical practice guidelines of the American Society for Parenteral Nutrition suggest that critically ill patients should receive enteral nutrition as soon as possible. Studies have shown that early enteral nutrition can effectively improve the nutritional status of critically ill patients.–13 However, during the period of enteral nutrition, patients often have feeding intolerance . The incidence of enteral nutrition intolerance is 30.5% to 65.7%.,15 This leads to the suspension of enteral nutrition and the inability of patients to take in adequate energy and nutrients, which seriously affects the nutritional status of patients. SAP is a common acute and critical illness in clinic. Due to massive extravasation of pancreatic juice, it can lead to multiple organ function damage, especially gastrointestinal function damage, which can easily lead to enteral nutrition intolerance.,18 Therefore, how to avoid the occurrence of feeding intolerance in SAP patients needs to be studied and discussed by nurses.In recent years, enteral nutrition has been given sufficient attention in the treatment of critically ill patients. Enteral nutrition can not only maintain the homeostasis of intestinal bacteria and keep the intestinal epithelium intact, but also repair the injured intestinal tract and reduce the intestinal injury.–24 The purpose of this study was to analyze the risk factors of enteral nutrition intolerance in patients with SAP by Meta, to provide reference for nurses to prevent and manage enteral nutrition intolerance in patients with SAP.At present, there are different reports on the influencing factors of enteral nutrition intolerance in patients with SAP.22.1This protocol has been registered on Open Science Framework grant number (registration number: DOI 10.17605/OSF.IO/YXJSM). This report will be based on the preferred reporting items for systematic review and meta-analysis protocols.2.22.2.11.Original studies on the effect of enteral nutrition intolerance in patients with SAP;2.Patients diagnosed with SAP, age ≥ 18 years old, regardless of gender and race;3.Studies whose results involve the specific values of relative risk (RR) and 95% confidence interval (95% CI) of risk factors.2.2.21.Studies that only have the abstract and cannot carry on the research of data extraction;2.Studies published repeatedly;3.Review, systematic review, conference, animal experiments, and other literatures;4.Studies that are unable to carry out the research of data conversion.2.3Studies delineating the enteral feeding intolerance in SAP patients were consistently and exhaustively searched using medical specialty databases of PubMed, Embase, Cochrane Library, Web of Science, China Biology Medicine Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, and Wanfang. The retrieval time was from the establishment of the database to March 2021. These search terms are summarized in Table 2.4The process of the selection is exhibited in Figure 2.5The data of the included literature were extracted independently by 2 evaluators. The specific contents of data extraction include: author, year of publication, type of study, sex, age, total sample size, number of patients in case group and control group, incidence of feeding intolerance, and risk factors of feeding intolerance.2.6 NOS score ≥ 6 means that the literature quality is better.Methodological quality of all studies was assessed using the Newcastle-Ottawa scale (NOS).2.7 If there is significant statistical heterogeneity, we will apply the DerSimonian-Laird random effect model. The data analysis of this study will be conducted through Review Manager 5.3 software.We will use RR and 95% CI to represent. If there are no findings of statistical heterogeneity, the Mantel-Haenszel fixed effect model is adopted for data synthesis.2.8I2 quantitative analysis. When P < .1, and (or) I2 > 50%, the random effect model is adopted for the combined analysis. Otherwise, the fixed effect model is adopted.The magnitude of heterogeneity in the results was determined by χ2 test and 2.9According to the study type, age, and region, we make a subgroup analysis.2.10Sensitivity analysis is to test the stability of meta results by changing the data analysis model.2.11Publication bias is analyzed by funnel chart.2.12The research was on the defects of the original data. We contacted the author by email and asked for the original data. If the original data were not available, we would analyze the existing data.2.13The content of this article does not involve moral approval or ethical review and will be presented in print or at relevant conferences.3 During SAP, the body is in a state of stress and high catabolism, and the energy consumption increases sharply, which is up to 1.2 to 1.5 times of the basic value and is prone to malnutrition and decreased immunity. Timely and efficient nutritional support has become an important link in the treatment of SAP. Enteral nutrition, as a nutritional support method in line with normal physiology, can not only avoid the stimulation of the pancreas by nutrient solution, but also achieve the purpose of pancreatic rest. It also helps to maintain intestinal mucosal epithelial barrier function, reduce intestinal bacterial translocation and endotoxin release, reduce inflammatory response, and improve patient prognosis.SAP is a common acute abdomen in the Department of Gastroenterology. It occurs rapidly and is critically ill, with a fatality rate as high as 20%.Patients with SAP have gastrointestinal dysfunction and are prone to enteral nutrition intolerance, which leads to the suspension or termination of enteral nutrition. How to individually predict, evaluate, and prevent the occurrence of enteral nutrition intolerance in patients with SAP is becoming an urgent problem to be solved in clinical work. In this study, meta-analysis was used to analyze the risk factors of enteral nutrition intolerance in patients with SAP, so as to provide evidence for clinical individualized intervention and risk prediction.Conceptualization: Hongyun Fan and Zhiying Duan.Data collection: Hongyun Fan and Chunchun Yang.Funding acquisition: Yang Yang.Resources: Chunchun Yang and Zhiying Duan.Software: Xiaohui Huo.Supervision: Xiaohui Huo and Yang Yang.Writing – original draft: Hongyun Fan and Chunchun Yang.Writing – review & editing: Hongyun Fan and Yang Yang.


Purpose: The current study aimed to investigate the normative data for blood pressure. Materials and Methods: From 2017 to 2020, 2032 men and women classified as ‘war veterans’ were recruited (mean age ± standard deviation (SD): 60.97 ± 7.98 years; mean stature: 172.50 ± 9.10 cm; mean body mass: 90.25 ± 36.45 kg; mean body-mass index: 29.66 ± 5.59 kg/m2; 29.9% women). Their systolic and diastolic blood pressures were measured three times. The procedure was carried out according to the American Heart Organization. The sex-specific and age-specific normative data for the 5th, 25th, 50th (median), 75th, and 90th percentiles for systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (measured as SBP-DBP) and mid-BP (the average of SBP and DBP) were presented. Results: The men had higher SBP (p < 0.001), DBP (p < 0.001), pulse pressure (p < 0.001) and mid-BP (p < 0.001) compared to the women. The age-specific differences showed that older individuals had higher values of SBP (p < 0.001), pulse pressure (p < 0.001), and mid-BP (p < 0.001), while no significant differences for DBP (p = 0.496) were observed. Conclusions: This is the first study providing sex-specific and age-specific normative data for blood pressure in war veterans. Blood pressure is an essential component of everyday systematic examination in humans. In clinical practice, systolic blood pressure (SBP) and diastolic blood pressure (DBP) are the most commonly reported measures . ObserviPrevious evidence reported that the global mean age-standardized SBP and DBP in the general population were 127.0 mm/Hg and 78.7 mm/Hg in men and 122.3 mm/Hg and 76.7 mm/Hg in women, with higher SBP and DBP observed in Central and Eastern Europe [Hypertension, defined as SBP ≥ 140 mm/Hg or DBP ≥ 90 mm/Hg, has become a public health burden worldwide . It 2010Measuring SBP and DBP by sex and age is the first step of the correct classification and identification of individuals at higher risk. Therefore, reference-based standards for such measures are needed. To date, only a handful of studies have investigated reference data for BP ,11,12,13Therefore, the current study aimed to investigate the normative data for systolic and diastolic blood pressure in a large sample of Croatian war veterans.acquis and mitigate the negative consequences of the Homeland War. The special goal refers to strengthening the care system and raising the quality of life of the veteran and suffering population through the activities of the Home of Croatian Veterans. The institution provides the user with the use of accommodation or accommodation services. The accommodation program includes the use of services during the provided accommodation in the Institution 24 h a day for up to 20 days. The program of stay implies the use of the services of the Institution during a full-day or half-day stay. A half-day stay can last up to 6 h a day. The full day stay can last from 6 to 10 h a day. The program of the stay does not include overnight stays in the Institution, and is intended for users who live near the Home and use the partial services of the Home. For the purpose of this study, we collected the data from 2017 to 2020 for all of the participants within the facility care. During the period of 4 years, approximately 2500 users used the accommodation service. Of these, 468 participants did not have their blood pressure measured and were excluded from further analysis. Our final sample consisted of 2032 facility users (29.9% women). Before the study began, all of the participants gave written informed consent for participation. All of the procedures were anonymous and in accordance with the Declaration of Helsinki, and were also approved by The Home for Croatian Veterans (Ethics code number: 2017/04).In this cross-sectional study, we recruited men and women who participated in a homeland war between Croatia and Serbia from 1990 to 1995. All of the participants were part of the Home for Croatian Veterans. The Home for Croatian Veterans is an accommodation and rehabilitation institution established by the Ministry of Croatian Veterans with the intention of improving and strengthening the provision of comprehensive care for the veteran and suffering population. The general goal of the Home of Croatian Veterans is to preserve the Blood pressure was measured three times in a sitting position after a 5 min rest period using a standard mercury sphygmomanometer blood pressure cuff, according to the American Heart Association’s standardized protocol . SpecifiThe basic descriptive statistics are presented as mean and standard deviation (SD). The Kolmogorov–Smirnov tests showed that the data were normally distributed. The sex and age differences were calculated by using analysis of variance (ANOVA) with a post hoc comparison test between the groups. For each variable, we determined sex-specific and age-specific percentile values  and used the Lambda (L), Mu (M) and Sigma (S) method, in which the optimal power to obtain normality is summarized by a smooth (L) curve, and trends in the mean (M) and coefficient of variation (S) are similarly smoothed. Next, all three curves  were summarized based on the power of age-specific Box–Cox power transformations for the normalization of the data. The LMS method assumes that the data can be normalized using a power transformation and by removing the skewness . The sexp < 0.001). Of note, no significant differences in blood pressure between the war veterans with and without diseases were observed (p = 0.174–0.486).The basic descriptive statistics are presented in F = 1, 2030) = 55.96, p < 0.001), DBP  = 35.41, p < 0.001) and pulse pressure  = 33.09, p < 0.001) compared to the women. The age-specific differences showed that older individuals had higher values of SBP  = 8.62, p < 0.001) and pulse pressure  = 15.98, p < 0.001), while no significant differences for DBP  = 0.90, p = 0.496) were observed. The sex and age interaction effect did not show significant differences in SBP  = 1.00, p = 0.424) and pulse pressure  = 0.46, p = 0.840), but a significant interaction in DBP  = 2.70, p = 0.013) was observed.r = 0.08, p = 0.003 and r = 0.18, p < 0.001), pointing out that older participants suffered more frequently from higher blood pressure. The most prevalent categories were ‘stage 1 hypertension’ and ‘stage 2 hypertension’ in both sexes. Furthermore, when observing SBP as a numerical value, a significant correlation with age was found , while DBP was not significantly correlated with age .The current study aimed to investigate the normative data for systolic and diastolic blood pressure for Croatian war veterans. The main findings are: (1) the men had higher SBP, DBP and pulse pressure, compared to the women; (2) older individuals had higher values of SBP and pulse pressure, while no significant differences for DBP were observed; and (3) the highest prevalence of ‘stage 1 hypertension’ and ‘stage 2 hypertension’ in both sexes was noted.This is the first study examining reference data for blood pressure parameters in war veterans. Indeed, cardiovascular diseases are the leading cause of mortality among male veterans in healthcare settings, and a higher prevalence of hypertension has been found in these individuals compared to general population . The aveOur results of the higher prevalence of hypertension are in line with previous studies ,18,19,20This study is not without limitations. First, blood pressure values should be obtained from longitudinal studies that give the possibility to assess natural changes in individual growth and development. Second, more detailed information about the environmental factors affecting blood pressure during the war was not collected, which might have led to different reference-based standards.In conclusion, this is the first study aiming to develop the normative data for systolic and diastolic blood pressure in Croatian war veterans. The reported normative values serve different purposes. Participants in higher percentiles should be a target group for special interventions aiming to decrease the level of their blood pressure. Second, baseline results can be easily tracked by remembering a certain percentile at the beginning and after a follow-up period.


The impact of blood pressure on neurological symptoms and risk of end-stage kidney disease (ESKD) is unknown in primary and secondary thrombotic microangiopathies (TMAs).We measured baseline systolic (SBP) and diastolic (DBP) BP in consecutive 563 patients with adjudicated primary and secondary TMAs, and assessed its association with the risk of ESKD.Normal BP, grade 1, 2 and 3 hypertension were present in 243 (43.1%), 132 (23.4%), 101 (17.9%) and 88 (15.6%), respectively.Significant BP differences were noted in relation to the cause of TMA: highest BP values were found in patients with atypical hemolytic-uremic syndrome (aHUS), pregnancy, transplantation and auto-immune-related TMAs. Normal BP or grade 1 hypertension was found in 17/18 (94.4%) patients with thrombotic thrombocytopenic patients (only 1/18 (5.6%) had a SBP value>150 mmHg). In contrast, BP values could not differentiate isolated “essential” malignant hypertension (MH) from MH associated with aHUS (isolated MH (n=15): BP (median (IQR)): 220 (182-249)/132 (101-150) mmHg; MH with aHUS (n=5): BP: 223 (196-245)/131 (111-144) mmHg).The risk of vigilance disturbances , epileptic seizures  and posterior reversible encephalopathy syndrome  increased with increasing baseline BP values from grade 1 to grade 3 hypertension.ESKD occurred in 35/563 (6.2%) patients . As compared to patients with normal BP (<120/139 mmHg), grade 1, grade 2 and grade 3 hypertension were associated with a greater risk of ESKD in univariate  and multivariate  analyses. The association between BP and the risk of ESRD was unchanged after adjustment on eculizumab use . Patients with MH, regardless of its cause, had a greater risk of ESKD (OR: 26.4 [10.0-69.8] vs other patients).Baseline BP differs in primary and secondary TMAs. High BP reduces the neurological tolerance of TMAs and is a powerful independent risk factor of ESKD, even after adjustment on TMA’s cause. Thrombotic microangiopathy (TMA) is a heterogenous group of diseases characterized by thrombocytopenia and mechanical hemolytic anemia with schistocytosis and elevated lactate dehydrogenase (LDH) . They reLittle is known regarding the relationship between blood pressure (BP) and TMAs. This issue has been overlooked as BP values are not even reported in large-scale TMA studies –8. NonetThe aim of the present retrospective study was to assess the association between baseline BP and causes of TMA, and to evaluate the impact of between baseline BP on renal survival in a large cohort of consecutive patients with a wide range of adjudicated TMA.st, 2009 and December 31st, 2016 were included. As previously described ), pregnancy (OR: 0.21 [0.05-0.94]), malignant hypertension (OR: 26.4 [10.0-69.8]) and transplantation (OR: 3.63 [1.78-7.44]) were significantly associated with ESRD in multivariate analyses (Table 4.7), prep<0.0001)  Fig..In univariate analyses, BP was a powerful risk factor for ESRD: there was a dose-response relationship across BP categories and the risk of ESRD Table . These rInterestingly, eculizumab was used in 10/15 (66.7%) of patients with aHUS. Of note, since 2012, only 1 patient with aHUS was not treated with eculizumab: she remained on dialysis . Importantly, aHUS was no longer a risk factor for ESRD when eculizumab and BP categories were entered into the models . Nevertheless, the association between BP and the risk of ESRD was unchanged after adjustment on eculizumab use (vs SBP<120 mmHg: OR (120-139 mmHg): 3.46 [1.41-8.49], p=0.0067); OR (140-179 mmHg): 17.7 [4.44-70.0], p<0.0001; OR .We assessed the epidemiological value of BP in a large cohort of patients with various types of TMAs. Files were individually reviewed and therefore identification of included patients was not based on administrative codes but careful analysis of clinical and biological data. All consecutive TMA cases were included, thus reducing selection bias. They were adjudicated by experienced physicians.Our first finding is that BP significantly differed across distinct causes of TMA. These differences allowed better identification of the causes of TMA. BP value at baseline was a powerful diagnostic tool: among patients with TTP, values of BP >150 mmHg for SBP or 100 mmHg for DBP virtually excluded the diagnosis of TTP . When no other obvious cause was present, these BP cut-off value allowed a strong suspicion of aHUS in most cases . The identification of the cause of TMA is crucial, and any delay negatively affects patient survival . Data onThe second finding is that there was a striking dose-response relationship between baseline BP and the risk of ESRD, regardless of the cause of TMA. Interestingly, the BP-related risk of ESRD was not restricted to patients with severe or malignant hypertension, and not even restricted to patients with hypertension as it started at a normal SBP value (120 mmHg). Moreover, BP remained the major parameter associated with the risk of ESRD in multivariate analyses. In 62 patients with TMA, Dierkes et al found that elevated arterial pressure was a risk factor for persistent renal disease . Jammes The nature of the relationship between BP and the pathophysiology of TMA is not clearly understood. Hypertension probably results from severe endothelial damage, a common feature to both TMAs and severe hypertension . HoweverInterestingly, neurological symptoms such as headaches, visual disturbances, seizures and PRES were frequently observed in patients with severe BP values, regardless of the cause of TMAs. These findings suggest that high BP plays a major role in the neurological tolerance of TMA. They also support the widespread view that BP lowering to normal levels must be achieved in hypertensive patients with TMAs to ensure a more complete recovery of TMA symptoms –25. AlteInterestingly, in a recent study in 20 patients with malignant hypertension, half of patients had low haptoglobin, and 12 patients had reversible encephalopathy syndrome. Among these 12 patients, 11 patients with reversible encephalopathy syndrome had both cortex and brainstem lesions. In addition, 6/7 patients with headache at presentation had reversible encephalopathy syndrome whereas 6/12 without headache had also reversible encephalopathy syndrome. These lesions disappeared after BP control .Autopsy studies revealed that microthrombi are present in the kidneys of most patients with TTP, typically affecting few segments of the glomeruli, but there is no significant renal infiltration of inflammatory cells in these patients unlike patients with other causes TMA and AKI in whom these lesions are more widespread and more severe , 31). ThThe results of the present study are robust but they come from a single institution, and therefore they need to be replicated using a prospective study design. The results of renal biopsies could certainly shed some light on the nature of the association between baseline BP and renal survival, as it was shown that some patients with specific causes of renal diseases (such as IgA nephropathy) can present with high BP and TMA, and that the risk of ESRD was elevated in this population . Kidney Our data indicate that TMAs, a group of severe hematological diseases, diversely affect the acute regulation of BP, and that BP should be carefully analyzed in patients with TMA. Epidemiological studies focused should report baseline BP values as these values provide valuable information regarding the identification of the cause of TMAs, which in turn can lead to reduction of delays in diagnosis and therapy and improved prognosis , 18, 33


Introduction: It has been suggested that dynamic arterial elastance (Eadyn) can predict decreases in arterial pressure in response to changing norepinephrine levels. The objective of this study was to determine whether Eadyn is correlated with determinants of the vascular waterfall [critical closing pressure (CCP) and systemic arterial resistance (SARi)] in patients treated with norepinephrine.Materials and Methods: Patients treated with norepinephrine for vasoplegia following cardiac surgery were studied. Vascular and flow parameters were recorded immediately before the norepinephrine infusion and then again once hemodynamic parameters had been stable for 15 min. The primary outcomes were Eadyn and its associations with CCP and SARi. The secondary outcomes were the associations between Eadyn and vascular/flow parameters.Results: At baseline, all patients were hypotensive with Eadyn of 0.93 . Norepinephrine increased the arterial blood pressure, cardiac index, CCP, total peripheral resistance (TPRi), arterial elastance, and ventricular elastance and decreased Eadyn [0.40 ] and SARi. Eadyn was significantly associated with arterial compliance (CA), CCP, and TPRi (p < 0.05).Conclusion: In patients with vasoplegic syndrome, Eadyn was correlated with determinants of the vascular waterfall. Eadyn is an easy-to-read functional index of arterial load that can be used to assess the patient’s macro/microcirculatory status.Clinical Trial Registration:ClinicalTrials.gov #NCT03478709. Indeed, it has been shown that Eadyn can predict (i) the increase in mean arterial pressure (MAP) following a fluid challenge , and arterial compliance hallenge . It is ahallenge . Howeverance CA; .dyn  in vasoplegic patients in the ICU has not previously been evaluated. Given that vasomotor manipulation changes CCP and SARi, we hypothesized that Eadyn indirectly reflects the status of these vascular waterfall components.The concept of vascular waterfall introduced the existence of a pressure gradient between the critical closing pressure (CCP) at the arteriolar level and the mean systemic filling pressure (MSP) at the venular level. The CCP has been described on the microcirculatory level and corresponds to the arterial pressure below which blood flow is stopped by occlusion of the arterioles . The CCPdyn . The assdyn is associated with the vascular waterfall components in post-operative cardiac surgery patients treated with norepinephrine. The secondary objectives were to assess the putative associations between Eadyn and several arterial load and blood flow variables.The main objective of the present study was to determine whether EaClinicaltrials.gov (NCT03478709). The present report was drafted in line with the STARD statement  and was registered at tatement . The stuWe performed a bicentric, prospective, observational study in the cardiothoracic and vascular ICU in two university hospitals. The inclusion criteria were as follows: adult patients admitted to the ICU and for whom the physician had decided, in accordance with the unit’s care protocols, to treat post-operative vasoplegic syndrome; monitoring with a central venous access and an invasive blood pressure measurement; and the presence of a sinus heart rate (HR). Vasoplegic syndrome was defined by persistent arterial hypotension despite fluid resuscitation , 2020. TWe measured the systolic blood pressure (SAP), diastolic blood pressure (DAP), and MAP using an invasive arterial catheter.Echocardiography  was performed by a physician who was blinded to the study outcomes. The left ventricular ejection fraction (LVEF) was measured using Simpson’s biplane method with a four-chamber view. The indexed stroke volume  was calculated by multiplying the left ventricular outflow tract’s (LVOT’s) velocity time integral (VTI) by the aortic area and dividing by body surface area (BSA). The cardiac index (CI) was calculated as SVi × HR.The respiratory SVV was calculated as (SVmax − SVmin)/[(SVmax + SVmin)/2] × 100.Mean echocardiographic parameters were calculated from five individual beat measurements (regardless of the respiratory cycle) and analyzed retrospectively by a senior cardiologist with echocardiography certification.−1·m−2) was calculated as (MAP − CCP)/CI. Indexed systemic venous resistance  was calculated as (MSP − CVP)/CI.The MSP and CCP were measured using the inspiratory breath-hold maneuver described by V) was estimated at the bedside by using the equation EV = MAP/, total net CA, characteristic impedance, and systolic and diastolic time intervals (A was estimated by using the equation EA = MAP/SVi (mmHg ml−1·m−2). This ratio has been shown to be a robust EA surrogate over a wide range of hemodynamic conditions and is interchangeable in any peripheral artery , and CA (ml mmHg−1·m−2) was calculated as SVi/arterial pulse pressure (PP).TPRi was calculated as (MAP − CVP)/CI  set of measurements was recorded after 15 min of hemodynamic stability (defined as a change in MAP of less than 10%). All patients had been sedated by continuous infusion of propofol and were fully adapted to mechanical ventilation. All patients were mechanically ventilated in pressure-controlled mode with a positive end-expiratory pressure (PEEP) of 5 cmHdyn and CCP higher than 0.5, using Spearman’s correlation coefficient with a risk alpha of 5% and a power of 80%. The distribution of the variables was assessed using the D’Agostino-Pearson test. Data are expressed as proportion (%), mean (standard deviation), or median [IQR] (interquartile range) as appropriate. Paired data were compared using Wilcoxon signed rank test. Linear correlations were tested using Spearman’s rank method. Associations between arterial load and blood flow parameters measurement considering both time points were assessed using mixed linear modeling. Only bivariate models were carried out. Eadyn was the dependent variable; each hemodynamic variable was used as fixed effect, and individual was used as random intercept. The normality of the distribution of random effects and of the model residual were graphically checked. Because this analysis was exploratory, slight disparities between those distributions and normality were tolerated. The threshold for statistical significance was set to 0.05. Statistical analysis was performed using RStudio Version 1.1.447-2009-2018 RStudio, Inc., and SPSS® software .We calculated that a sample size of 14 patients would allow to demonstrate a correlation between Ea−1·min−1 . None of the patients had been treated with inotropic agents or vasopressors before enrolment in the study.Twenty patients were included during the study period. Three were excluded because of incomplete data, and so 17 were included in the final analysis. Most of the study participants were male (80%). The median age was 68 , and the median Euroscore 2 was 2.3  . The meddyn values .At baseline, patients had arterial hypotension, with low CCP and CI values, and high SARi, SVV, PPV, and Ean values . Infusioand SARi . These cdyn was significantly and negatively correlated with CCP , CCP-MSP , SARi , SAP , DAP , MAP , EA , CA , and TPRi .In the overall study population, Eadyn demonstrated that Eadyn was significantly associated with CA, blood pressure, CCP, and TPRi . Furthermore, we confirmed that Eadyn is associated with several components of arterial load (CA and TPRi) and blood pressure (MAP and CCP).The present study’s main finding was the association between EaAccording to the concept of macrocirculatory-microcirculatory coherence, any change in the macrocirculation will affect the microcirculation . Hence, When arterial hypotension occurs, the main adaptive mechanism is the maintenance of blood flow to the tissues. In this respect, it has been suggested that several adaptive hemodynamic factors are activated so as to maintain the blood flow redistribution . The blodyn after norepinephrine infusion contrast with those observed upon norepinephrine weaning in the patients with sepsis or after cardiac surgery , and a decrease in arteriolar vasomotor tone  to predict arterial pressure changes , and thus to determine which treatments could be used or withdrawn. dyn predicts changes in MAP upon fluid expansion or vasopressor administration. In contrast to the complex procedures required to measure the vascular waterfall and arterial load variables, Eadyn is easy to measure with hemodynamic devices – even an uncalibrated pulse contour analysis device  following treatment. Hence, one can consider that Eadyn reflects vasomotor tone in hypotensive patients treated with norepinephrine. In view of our present results and the literature data, one can further consider that Eadyn indirectly reflects macro-microcirculatory coherence during acute circulatory failure.In hypotensive patients treated with norepinephrine, EaThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Comité de Protection des Personnes Est II, Besançon, France; reference: 17/07, June 19th, 2017. The patients/participants provided their written informed consent to participate in this study.SB, MN, P-GG, OA-A, and BB designed the study and interpreted the data. SB and P-GG analyzed the data. SB, P-GG, and HD drafted the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The efficacy of mepolizumab has been largely demonstrated in clinical trials in patients with severe eosinophilic asthma (SEA). However, reports on experience with mepolizumab in a real-life cohort are limited. Moreover, data about the effectiveness of mepolizumab on small airways is scarce. This study evaluated the effectiveness of mepolizumab therapy on symptoms, asthma exacerbations, blood eosinophils, steroid dependence, and small airways in a real-life cohort of patients with SEA.We retrospectively analyzed patients with SEA who were receiving fixed-dose mepolizumab. The effects of mepolizumab on clinical, laboratory, functional parameters were evaluated at 12th, 24th, and 52nd weeks. Small airways were assessed with the FEF 25-75.1 and FEF25-75 values at baseline, 12th, 24th, and 52nd weeks  A total of 41 patients were enrolled in the study. Mepolizumab significantly reduced asthma exacerbation rates, reduced mOCS dose, and improved asthma control test (ACT) scores at 12th, 24th, and 52nd weeks. However, we found no significant changes in FEV1 and FEF25-75 values.  In this study, mepolizumab significantly improved all outcomes  except functional parameters. Still, despite the dose reduction in mOCS dosage, no significant deterioration was observed in FEV Eosinophilic asthma generally refers to the clinical inflammatory phenotype of asthma wherein a significant number of sputum, airway, and/or blood eosinophils are present [1]. Eosinophils are key effector cells in bronchial inflammation and represent one of the main targets for biological agents. Interleukin-5 (IL-5) is the pivotal cytokine responsible for the maturation, activation, proliferation and survival of eosinophils . Therefore, IL-5 represents a suitable specific target for biological treatments of severe eosinophilic asthma (SEA). Mepolizumab is a humanized IgG1/k monoclonal antibody which targets human IL-5 and thus prevents its interaction with the α chain of the IL-5 receptor . Previous effectiveness studies of mepolizumab have clearly demonstrated that mepolizumab caused a meaningful lowering effect on blood eosinophils, was able to reduce asthma exacerbation rates, had a significant glucocorticoid-sparing effect and improved symptom control in asthma [6–9]. On the contrary, data regarding post-marketing studies that have evaluated the effects of mepolizumab in real-life settings are limited. Furthermore, the data about the effectiveness of mepolizumab therapy on small airways is quite limited in patients with SEA. Therefore, we evaluated effectiveness of mepolizumab on symptoms, asthma exacerbations, blood eosinophils, steroid dependence, and small airways in the real-life settings. 2-agonist, along with a second controller montelukast at least 6 months and most of patients were receiving mOCS therapy before the mepolizumab treatment. Indications to be treated with mepolizumab were approved on the basis of the Turkey Social Security Institution Health Application Communique, according to which, mepolizumab can be administered to patients with SEA having: a) blood eosinophil count ≥300 cells/µL (≥150 cells/µL: If the patient is under long-term regular OCS therapy); b) controlled or uncontrolled asthma treated with regular systemic steroids for at least 6 months and/or uncontrolled asthma (relatively two attacks per year requiring systemic corticosteroids for at least 3 days) despite use of a high combination dosage of ICS  and inhaler long-acting β2 agonist for at least one year [10].1Turkey Social Security Institution Health Application Communique. [Online]. Websıte: https://www.mevzuat.gov.tr/mevzuat?MevzuatNo=17229&MevzuatTur=9&MevzuatTertip=5 .This retrospective study included 41 severe asthmatics who had been treated with mepolizumab between 2018 and 2020. All patients were treated with high-dose inhaled glucocorticoids (ICS) , and a long-acting β1) and FEF25-75 were measured at baseline, at week 12, at week 24, and at week 52 after the first injection of mepolizumab. In addition, the numbers of asthma exacerbations were also recorded at baseline, week 24, and week 52 . Throughout the study period, parameters including mOCS , asthma control test (ACT) score, blood eosinophil count, forced expiratory volume in 1 s  . The dose of methylprednisone was reduced every four weeks according to a predefined schedule (Table 1), if the patient did not have an exacerbation with a decrease in ACT score. In patients who were receiving a daily dose of 8 mg or more of methylprednisone at baseline, the dose of the drug was not reduced to 0 without consulting to endocrinology due to concern regarding withdrawal effects.1 (Forced expiratory volume in 1 s), FVC , FEV1/FVC, FEF25-75 values were measured and presented as the percentage of the expected value, according to the patient’s age and height. Pulmonary function tests were performed at the Erciyes University Medical Faculty Chest Diseases outpatient clinic by trained and experienced respiratory function test technicians of at least 5 years using a Vmax 20c spirometre device while the patients were at a sitting position. Following at least 3 acceptable maneuvers of the pulmonary function test, the best test was recorded. FEVData were entered into Statistical Package for Social Sciences software v: 17.0 , and analyses were made using the same software program. The distribution of continuous variables was tested with the one-sample Kolmogorov– Smirnov test, and the data are shown as mean ± standard deviation or median and minimum–maximum intervals. For all parametric variables, between group comparisons were made by using repeated measures Anova. For all nonparametric variables, between group comparisons were made by Friedman test, and Dunnett’s multiple comparison test was made within groups when the difference was statistically significant. A p value of < 0.05 was considered to be significant in all analyses.1 and FEF25-75 values before mepolizumab treatment found as 78.9 ± 23.2%, and 45.1 ± 23.1%, respectively. Of the 41 patients, 35 (85.4%) were receiving mOCS therapy before mepolizumab, with a median dose of 4 mg. The median eosinophil count at baseline was 450  cells/µL.This study included 41 severe asthmatic subjects . Baseline demographics were presented in Table 2. Mean ACT scores were 16.6 ± 4.8 points at baseline. FEV1 values were observed at this time point (78.9 ± 23.3% vs 82.5 ± 23.7%).Of the patients, 34/41 (83%) were continued the mepolizumab treatment after 12 weeks. Seven patients were not included in the 12 weeks assessment for mepolizumab efficacy  . When comparing the change in blood eosinophil counts, mOCS doses and ACT scores between baseline and at week 12 under mepolizumab treatment, a marked decrease in peripheral eosinophil counts (3.7 (0.1–18)% vs. 1.3 (0.2–2.8)%; p < 0.001) and an increase in ACT scores (17 (7–25) vs. 23 (14–25); p < 0.001) were observed. At week 12, all of the patients were classified as treatment responders according to increased ACT scores and decreased peripheral eosinophil counts or decreased OCS dose without clinical deterioration. mOCS dose was decreased in 27 of the 34 patients (79.4 %); oral corticosteroids were completely withdrawn in five of the 34 patients. No marked changes in FEVA total of 31/34 (91%) patients continued the mepolizumab treatment after 24 weeks. Three patients were not included in the 24 weeks’ assessment for mepolizumab efficacy  . Of the responders, 31/33 (94%) were still responders at the 24th weeks’ assessment. After the 24th week under mepolizumab treatment, the decrease in blood eosinophil counts (baseline eosinophil count: 3.7 (0.1–18); 24th week eosinophil count: 1.2 (0.2–4.7)%; p < 0.001) and improvement in ACT scores (baseline ACT: 17 (7–25); 24th week ACT: 24 (15–25); p < 0.001) were continued. mOCS dose was additionally reduced in 15 patients when comparing to 12th week results. Daily oral corticosteroid dose was withdrawn in 4 additional patients at week 24. When compared to baseline, at week 24, a significant decrease in the exacerbation rates within the last 24 weeks was observed (1 (0–8) vs. 0 (0–0); p < 0.001).A total of 21/31 (68%) patients continued mepolizumab treatment after 52 weeks. Ten patients were not included in the 52 weeks’ assessment for mepolizumab efficacy  . Of the responders, 21/22 (95%) were still responders at the 52 weeks’ assessment. After 52 week under mepolizumab treatment, the decrease in blood eosinophil counts  and improvement in ACT scores (baseline ACT: 17 (7–25); 52nd week ACT: 24 (17–25); p < 0.001) continued. mOCS dose was additionally reduced in five patients when comparing to 24th week results. In total, the OCS dose of 18/21 (85.7%) patients could be reduced at the end of 52 weeks. mOCS treatment was withdrawn in four additional patients at week 52. In total, 11/21 (52%) patients were able to discontinue mOCS at the end of 52 weeks. At this time point a significant decrease in the exacerbation rates within the last 52 weeks was observed when compared to baseline (1 (0–8) vs. 0 (0–3); p < 0.001). Comparison of mOCS dose, number of asthma exacerbations, ACT scores, and peripheral blood eosinophils at the beginning of mepolizumab and at 12th, 24th, and 52th weeks after treatment was shown table Table 3. 1 values at 12th, 24th, and 52th weeks showed no significant change when compared to baseline values . Also, no marked changes in FEF25-75 values between the baseline and at 12th, 24th, and 52nd weeks were observed . Comparison of FEV1, FEF25-75 at the beginning of mepolizumab and at 12th, 24th and, 52nd weeks after treatment was shown in Figure 3a and Figure 3b, respectively. FEV1 and FEF25-75 values with 52-week mepolizumab add-on treatment. Our study showed that mepolizumab therapy reduced the rate of asthma exacerbations, decreased mOCS dose, improved ACT scores, and decreased peripheral blood eosinophil counts in patients with SEA. On the contrary, we found no marked changes in FEV1 values after 12, 24, and 52 weeks of mepolizumab treatment, compared to baseline in agreement with some studies . Yet, the important point here is that there was no deterioration in pretreatment FEV1 values, and improved ACT scores despite dose reduction or discontinuation of OCS. We suggested that SC fixed-dose mepolizumab administration significantly decreased blood eosinophil levels, asthma exacerbations, mOCS doses and improved ACT scores in patients with SEA in agreement with the placebo-controlled studies and real life studies . There were no significant change in FEV1 . Contrary to our expectation, we didn’t find any significant improvement in FEF25%–75% with mepolizumab effect on small airways. However, there was no deterioration in pretreatment FEF25-75 values despite dose reduction or discontinuation of OCS. To the best of our knowledge, there are only two studies evaluating the effect of mepolizumab on small airways in the literature. In the first study conducted by Farah et al, mepolizumab could significantly improve small airways in SEA measured with multiple breath nitrogen washout [22]. The improvement in small airway function was associated with asthma control in the study [22]. Unlike this study, the absence of changes in small airways in our study may result from small airway assessment method differences. The nitrogen washout method may be more sensitive than the FEF25-75 measurement in detecting the change in small airways in patients receiving mepolizumab treatment . On the other hand, our study cohort differed from this study cohort. At baseline, our patient population were younger and most of the patients was using mOCS, had nasal polyposis and higher FEV1 values. In the second study, Sposato et al. showed that FEF25-75 improved after mepolizumab therapy in patients with SEA on the contrary to our results [25]. Although both studies had similar patient cohorts, different results were obtained. As an explanation of this different results might be due to the low number of patients in our study. Another explanation is that the mOCS doses could be reduced rapidly within 3 months in majority of our cases because there was a significant increase in the symptom scores of the patients and the absence of asthma exacerbation. This decreasing continued until the end of the 52nd week. Therefore, while the dose of OCS can be reduced, we also reduce the improving effect of OCS on small airways. The small airway impairment, as assessed with FEF25-75 and might contribute to long-term persistent asthma and the subsequent risk for poor asthma outcomes, independently of large airway status [19]. Therefore, we evaluated mepolizumab effectiveness on small airways with mid expiratory flow rates. Despite no unanimous consensus on the algorithm to assess small airway function and structure, several noninvasive techniques can detect small airway dysfunction. FEF25-75 is generally thought to be more reflective of small airways obstruction than is FEVThe limitation of the present study was its retrospective design. Another limitation is that the lack of validity of the FEF25-75 measurement to reflect small airway functions and inflammation . However, The FEF25–75 is the spirometric variable most commonly cited as an indicator of small airway obstruction in literature [28]. The small airways were evaluated retrospectively with FEF25-75 values in our study. If it was a prospective study and our primary aim was to evaluate small airways, we could make a comparison using one of the other methods to evaluate small airways. In this way, we could more clearly evaluate the effect of mepolizumab on small airways.In conclusion, mepolizumab has been shown to be effective in reducing exacerbations and daily doses of mOCS in this real-life cohort of patients with SEA. Although we found no improving effect of mepolizumab therapy on small airways assessed with mid expiratory flow rates there was no significant deterioration compared to pretreatment FEF25-75 values, and there were improved ACT scores despite dose reduction or discontinuation of mOCS. Further studies comparing the effectiveness of mepolizumab treatment on the small airways with different techniques are needed. All patients were under follow-up at our asthma outpatient clinic provided written informed consent.