Is nasal continuous positive airway pressure (NCPAP), nasal intermittent positive pressure ventilation (NIPPV), or noninvasive high-frequency oscillatory ventilation (NHFOV) more beneficial in reducing invasive mechanical ventilation (IMV) in neonates?This secondary analysis of a randomized clinical trial involving 1137 neonates found that neonates receiving NIPPV or NHFOV had fewer reintubations , fewer early (within 48 hours after extubation) reintubations , and shorter duration of IMV  than those supported with NCPAP.These results suggest that NIPPV and NHFOV are essentially similar, and better than NCPAP, in terms of reintubation and duration of IMV in extremely preterm neonates and those with more severe respiratory failure. This secondary analysis of a randomized clinical trial examines whether noninvasive high-frequency oscillatory ventilation (NHFOV) is better than nasal intermittent positive pressure ventilation (NIPPV) and nasal continuous positive airway pressure (NCPAP) in reducing the duration of invasive mechanical ventilation in extremely preterm infants and those with severe respiratory failure. 2 levels).The NASONE  trial showed that noninvasive high-frequency oscillatory ventilation (NHFOV) slightly reduces the duration of invasive mechanical ventilation (IMV) in preterm infants, whereas NHFOV and noninvasive intermittent positive pressure ventilation (NIPPV) result in fewer reintubations than nasal continuous positive airway pressure (NCPAP). It is unknown whether NHFOV is similarly effective in extremely preterm neonates or in those with more severe respiratory failure  in China. Participants included neonates enrolled in the NASONE trial between December 2017 and May 2021 and belonging to 3 predefined subgroups: (1) born at less than or equal to 28 weeks’ (plus 6 days) gestation, (2) invasively ventilated for more than 1 week from birth, and (3) with CONCPAP, NIPPV, or NHFOV since the first extubation and until NICU discharge, with airway pressure higher in NHFOV than in NIPPV and than in NCPAP.The co–primary outcomes were total duration of IMV during the NICU stay, need for reintubation, and ventilator-free days calculated as per the original trial protocol. Outcomes were analyzed on an intention-to-treat basis as for the whole trial, and subgroup analyses followed the original statistical plan.2 greater than 50 mm Hg before or in the 24 hours after extubation. Both NIPPV and NHFOV were associated with significantly fewer reintubations  and early reintubations  than NCPAP, and these reintubations were less frequently due to refractory hypoxemia. IMV was shorter in the NIPPV and NHFOV groups  than in the NCPAP group. Co–primary outcomes were not different between NIPPV and NHFOV; there was no significant interaction effect. Infants in the NHFOV group showed significantly less moderate-to-severe bronchopulmonary dysplasia than infants in the NCPAP group  and better postextubation gas exchange in all subgroups. The 3 interventions were provided at different mean airway pressure and were equally safe.Among 1137 preterm infants, 455 (279 boys [61.3%]) were born at 28 weeks’ gestation or less, 375 (218 boys [58.1%]) underwent IMV for more than 1 week from birth, and 307 (183 boys [59.6%]) had COThe subgroup analyses of extremely preterm or more ill infants confirm the results obtained in the whole population: NIPPV and NHFOV appeared equally effective in reducing duration of IMV compared with NCPAP.NCT03181958ClinicalTrials.gov Identifier:  In fact, it is likely that 1 solution does not fit all and that respiratory support needs to be tailored to gestational age and clinical severity.Invasive mechanical ventilation (IMV) is a life-saving intervention for preterm neonates but is associated with negative outcomes, such as bronchopulmonary dysplasia (BPD) and later neurologic impairment.3 One of the biggest neonatal ventilation trials ever conducted (1440 enrolled patients), NASONE received independent public funding4 and used as much as possible the rigorous methods of pharmacological trials, as well as field training on the interventions.3 The trial was also pathophysiology based, because NHFOV and NIPPV management was guided by respiratory physiology and mechanics10 to generate higher mean airway pressure than in the NCPAP group. The NASONE study found that NHFOV slightly reduces the duration of IMV, whereas both NHFOV and NIPPV provide a lower risk of reintubation compared with NCPAP, and that the 3 respiratory support techniques were equally safe.11 These results were obtained in patients with gestational age less than or equal to 32 weeks, but the NASONE protocol3 anticipated some predefined subgroup analyses for certain categories of patients. These were the extremely preterm (≤28 weeks’ gestation) neonates and those with more severe respiratory failure. The latter group was defined as those undergoing IMV for at least 1 week continuously from birth or with CO2 greater than 50 mm Hg before or in the 24 hours after extubation. Patients with these characteristics are more likely to require long IMV.13 These subgroups were chosen by consensus between the investigators to identify patients who were more likely to undergo IMV.14The NASONE  study was a multicenter, assessor-blinded, randomized clinical trial investigating, from primary extubation until discharge from the neonatal intensive care unit (NICU), the use of noninvasive high-frequency oscillatory ventilation (NHFOV) vs nasal continuous positive airway pressure (NCPAP) vs unsynchronized noninvasive intermittent positive pressure ventilation (NIPPV) to reduce the duration of IMV.15 We report the results of the predefined subgroup analyses of the NASONE trial: we hypothesize that NHFOV, when used from primary extubation until NICU discharge, is more efficacious than NCPAP or NIPPV in reducing the need for IMV in extremely preterm neonates or in those with more severe respiratory failure.Clinical algorithms integrating respiratory support have been proposed to personalize the assistance of extremely preterm neonates, but we need evidence-based data to refine them.3 and all methodological details are available there and in CONSORT) reporting guidelines for multigroup trials.16The trial protocol was previously published,11 The trial was originally powered to detect a 20% reduction in IMV duration for NHFOV-treated patients.3Sixty-nine third-level referral NICUs in China participated. Between December 2017 and May 2021, using a software-generated random number sequence posted on a dedicated website, neonates were quickly randomized to receive NCPAP, NIPPV, or NHFOV, when extubation was imminent (within 1 hour). Randomization was not performed earlier to avoid any bias due to knowledge of the assigned intervention. Patients were allocated to a study group immediately after extubation and until NICU discharge . Devices and interfaces used to provide the respiratory support have been described elsewhere.3 we subdivided the NASONE population into 3 groups of neonates: (1) those born at a gestational age 28 weeks plus 6 days (28+6) or earlier or after 28+6 weeks, (2) those invasively ventilated for less than 1 week or 1 week or longer continuously from birth, and (3) those with CO2 less than or equal to or greater than 50 mm Hg before or in the 24 hours after extubation . The subgroups of neonates of gestational age 28 weeks or less or invasively ventilated for 1 week or longer continuously from birth or having CO2 greater than 50 mm Hg were considered as subgroups of interest.According to the predefined criteria,3), and (3) ventilator-free days (VFD) calculated as per the trial protocol.3 We also studied the need for early  reintubation, because this is considered likely to be directly linked to the original respiratory disorder.19 These outcomes address the global burden of care due to IMV, because they describe it from different clinical standpoints.For the subgroups of interest, we analyzed and reported the same co–primary outcomes chosen for the whole trial: (1) total duration of IMV during the NICU stay, (2) need for reintubation  and safety, including prevalence of air leaks and apneic events, patient comfort, weekly weight gain, prevalence of severe nasal skin injury, grade III to IV intraventricular hemorrhage, stage II to III necrotizing enterocolitis, and retinopathy of prematurity, if retinopathy of prematurity grade was more than 2 outcomes. The definitions and monitoring strategies for these outcomes were previously described.2 test and 1-way analysis of variance followed by the Sidak post hoc test, adjusting for multiple comparisons . Outcomes were analyzed on an intention-to-treat basis as for the whole trial and subgroup analyses followed the original statistical analysis plan.11 In detail, for dichotomous outcomes, we calculated a risk difference (95% CI), whereas for continuous outcomes, we calculated the mean difference (95% CI) between the groups. The need for reintubation was also studied with Kaplan-Meier analysis contrasted with the log-rank test. Interaction analyses for the co–primary outcomes were performed with Cox or linear regressions for dichotomous (reintubations) or continuous variables (duration of IMV or VFD), respectively; an interaction term between the study intervention and the variable used to define subgroups was inserted per each regression model, and results were reported as hazard ratio (95% CI) or β (95% CI) for dichotomous or continuous variables, respectively.22 The number needed to treat (NNT) was also calculated, where appropriate. Following the European Medicines Agency guidelines on the investigation of subgroups in clinical trials,23 data from all subgroups were presented together and visually analyzed using multiple forest plots, which were obtained using Open Meta-Analyst 10.1.24 Statistical analyses were performed with SPSS statistical software version 16 (IBM) and GPower software version 3.1.9.6 (University of Dusseldorf). Two-sided P < .05 was considered statistically significant.Data analysis was performed in August 2022. Basic patient characteristics were compared between the study groups, within each subgroup of interest, using χ2 greater than 50 mm Hg before or in the 24 hours after extubation  were born at 28 weeks’ gestation or less, 375 (218 boys [58.1%]) underwent IMV for 1 week or longer from birth, and 307 (183 boys [59.6%]) had COP values for comparisons are shown in the eAppendix in P values for comparisons are shown in the eAppendix in 2 compared with the NCPAP group in neonates of gestational age 28 weeks or less and in those invasively ventilated for at least 1 week. Similar results were observed for NIPPV in neonates ventilated for at least 1 week  both NIPPV and NHFOV were associated with fewer reintubations, fewer early reintubations, and shorter IMV duration compared with NCPAP in all subgroups of interest; (2) NHFOV was associated with less moderate-to-severe BPD than NCPAP in all subgroups of interest; (3) patients treated with NHFOV showed significantly better postextubation gas exchange than those treated with NCPAP or NIPPV, consistent with data showing that reintubations were less frequently due to refractory hypoxemia in the NHFOV group ; and (4) NCPAP, NIPPV, and NHFOV were equally safe. These results confirm the main NASONE trial results and help tailoring the respiratory support strategy to extremely preterm or severely ill infants.This secondary analysis of a randomized clinical trial was focused on extremely preterm neonates and those with more severe respiratory failure given their higher risk of negative outcomes. We found results similar to those reported in the whole population.15 Conversely, we can consider that NIPPV and NHFOV are essentially similar, and better than NCPAP, in terms of reintubation and total duration of IMV during the whole NICU stay. These results are similar to those obtained in the whole population,11 as essentially there is no interaction effect. The effect size in the subgroups of interest seems slightly bigger than that of the whole population.11 In fact, extremely preterm or more ill infants treated with NIPPV or NHFOV have a reintubation risk reduced by 15% to 28% and an IMV duration shortened by 2.3 to 5.0 days . We used 3 co–primary outcomes to describe the need for reintubation and IMV from various points of view and be as comprehensive as possible. Our findings are consistent with previous trials26 reporting fewer reintubations with NHFOV or NIPPV. The effect of NIPPV and NHFOV may be clinically relevant because every additional day of IMV27 and each reintubation28 have been associated with various negative outcomes in similar populations; of note, 2 days of IMV has been associated with significantly increased neutrophil influx into the alveoli.29The hypothesis that, in these subgroups, NHFOV would be more efficacious than the other techniques to reduce the duration of IMV is disproven. Because there are several respiratory techniques available, it is clear that there is no single solution for all patients.30 have compared ventilatory techniques at equal airway pressure and, unsurprisingly, have not reported any advantage because this prevents full exploitation of the potential of NIPPV and NHFOV. Several findings suggest that a ventilatory strategy with high airway pressure may be crucial to the improvement of respiratory outcomes11 and that increasing airway pressure reduces extubation failure also during NCPAP.31 Therefore, the higher airway pressure and alveolar recruitment maneuvers allowed in the NHFOV group, rather than the ventilatory mode itself, might be responsible for the results. The high airway pressure may have reduced the proinflammatory trigger represented by IMV.32 Furthermore, decreasing reintubations may reduce the occurrence of ventilator-associated pneumonia, which can also increase the risk of BPD.33 It was simple to allow higher airway pressure in NHFOV, although this might also be provided with a conventional technique, such as NIPPV. This, however, would require synchronization, which is unfortunately unavailable in most neonatal ventilators. Interestingly, the early use of invasive HFOV was also associated with reduced prevalence of BPD, although the evidence was weakened by inconsistency across trials and the variable case mix of the studied populations.34 Several factors, such as different ventilatory strategies and individual patient characteristics, may have interacted and influenced the efficacy of HFOV on a population level. The NASONE subgroup analysis overcomes, at least partially, these factors because it focuses on homogeneous subgroups of patients and applies NHFOV with a well-defined, physiology-based strategy, without any crossover.3 Moreover, subgroups were selected according to simple clinical criteria, which facilitates the patient bedside identification.NHFOV seems to be associated with reduced prevalence of moderate-to-severe BPD and better postextubation gas exchange in all subgroups of interest: this might be explained with the physiology-based ventilatory approach of the NASONE trial. In fact, NHFOV was used with airway pressure higher than in the other groups and using lung recruitment maneuvers, as is usually done during invasive HFOV, without any crossover. Previous trials37 Because the respiratory support technique was applied until NICU discharge, these data indicate the efficacy of NIPPV and NHFOV in reducing apneic events overall, not only for a short period following extubation. Nonetheless, the absolute effect size is small, and it is unclear whether this finding can be clinically meaningful. Our findings also showed the equal safety of the 3 trialed techniques in all subgroups.11 A higher risk of air leaks, nasal trauma, or discomfort has been excluded, and this is also consistent with data from smaller and shorter NHFOV trials and a recent cross-sectional study showing that NHFOV provides good patient comfort, which was not negatively influenced by the increasing airway pressure.38 Because crossover was not allowed, we cannot clarify whether patients started on NCPAP would still respond to alternate techniques when NCPAP fails. Nonetheless, the study demonstrates the safety of the trialed techniques; thus, treating with NIPPV or NHFOV an infant for whom NCPAP would not have failed may not entail any relevant harm.We also observed a lower incidence of apneas during NIPPV and NHFOV, consistent with what has been suggested in smaller or shorter studies.11 Furthermore, although it was performed with a strict method, this work consisted of many subgroup analyses about 3 study interventions, and sample size calculation was originally performed for one of the co–primary outcomes. Some results may be due to chance as analyses may have reduced power, particularly for the comparisons involving the smaller subgroups: thus, further dedicated trials may be needed to generalize these findings. A center effect has been minimized, but not totally excluded. The definitions of subgroups can be criticized because they were pragmatically chosen to facilitate the recruitment and did not use any complex metrics or tools to characterize patient pathophysiology. The results, notably those regarding moderate-to-severe BPD (which was only a secondary outcome), should be confirmed in specifically designed trials. Subgroups of interest were slightly imbalanced for birth weight, but the NHFOV group had the lowest mean weight; thus, positive results obtained in this group were observed despite this imbalance. Although we comprehensively described the need for IMV with several end points, the trialed intervention might only indirectly affect the total IMV duration because it may be influenced by concurrent factors, including extrapulmonary prematurity-related complications. However, these complications were similar between the groups, and we reduced this influence by using fixed extubation and reintubation criteria, as well as by avoiding crossover.3 The improvement in gas exchange and apneas observed with NHFOV is of uncertain clinical value given the small absolute effect, although it is consistent with findings observed in co–primary outcomes. Finally, the exposition to high airway pressure level may deserve further studies to ascertain its long-term safety. The NASONE population consisted of exclusively Chinese infants born at 25 weeks’ or later gestation who did not often receive steroid prophylaxis, remained on IMV for an average of 4 days from birth, and had a relatively high BPD incidence, irrespective of the study interventions. These peculiarities may have influenced our results, particularly for BPD, which may change if its a priori risk is lower.39 Thus, the results cannot be directly generalized to populations with different characteristics or to NICUs with different expertise. However, in the NASONE population, the use of IMV and the BPD rate are also quite similar to those of other recent trials, demonstrating that there is a real difficulty in improving this clinical problem.Limitations of this study include those related to the original design of the NASONE trial.In this study, neonates born extremely preterm or with more severe respiratory failure had fewer reintubations, fewer early reintubations, and shorter IMV duration if they received NIPPV or NHFOV, rather than NCPAP, from extubation until NICU discharge. NHFOV may also be associated with less moderate-to-severe BPD than NCPAP. NIPPV and NHFOV are as safe as NCPAP. These findings are similar to those of the whole NASONE population and help tailor respiratory support during NICU stay.


Notably, oxygen pulse was blunted due to an insufficient increase in both stroke volume  and peripheral oxygen extraction . Chronotropic incompetence was more prevalent in PAD patients and persisted after correction for beta-blocker use . Conclusions: In PAD patients, exercise limitation is associated with diastolic dysfunction, chronotropic incompetence and peripheral factors.Aim: We used a combined stress echocardiography and cardiopulmonary exercise test (CPET) to explore effort intolerance in peripheral arterial disease (PAD) patients. Methods: Twenty-three patients who had both PAD and coronary artery disease (CAD) were compared with twenty-four sex- and age-matched CAD patients and fifteen normal controls using a symptom-limited ramp bicycle CPET on a tilting dedicated ergometer. Echocardiographic images were obtained concurrently with gas exchange measurements along predefined stages of exercise. Oxygen extraction was calculated using the Fick equation at each activity level. Results: Along the stages of exercise , in PAD + CAD patients compared with CAD or controls, diastolic function worsened ( Peripheral arterial disease (PAD) affects 6.5% of people aged 50–55 years in the Western world, and its prevalence reaches 13% in those aged 70–75 years . PAD is Consecutive PAD patients who also had CAD  and experienced from lower extremity pain underwent combined SE with CPET as part of an investigation for effort intolerance at our center. Diagnosis of PAD was based on the following: extra-cranial carotid artery stenosis > 50%, abdominal aortic aneurysm, ankle–brachial index (ABI) < 0.9 or the need for peripheral arterial revascularization . All patTwo groups of consecutive age- and sex-matched patients who were referred for effort dyspnea assessment during the study period were used as controls: (I) patients with established CAD  , and (II) 15 normal controls. The 3 groups were matched according to age and sex, and the PAD + CAD group was matched with the CAD group according to major comorbidities, as described below. All study participants were ambulatory and stable. The trial was approved by our local ethics committee and all patients signed an informed consent.The study protocol included a combined SE with CPET and was previously described .2 max) was the highest averaged 30 s VO2 during exercise and was estimated on the basis of patients’ age, height, weight and sex. Work rate increment necessary to reach patients’ estimated VO2 max in 8 to 12 min was then calculated. The protocol included 3 min of unloaded pedaling, a symptom-limited ramp graded exercise and 2 min of recovery. Breath-by-breath minute ventilation, carbon dioxide production (VCO2) and oxygen consumption (VO2) were measured using a Medical Graphics metabolic cart . The RER was defined as the ratio between VCO2 and VO2 obtained from ventilatory expired gas analysis [A symptom-limited graded ramp bicycle exercise test was performed in the semi-supine position on a tilting dedicated microprocessor-controlled eddy current brake SE cycle ergometer . Expected maximal oxygen consumption . Each cycle of imaging included left ventricular end-diastolic and end-systolic volumes, stroke volume (SV), peak E- and A-wave velocities, deceleration time and septal e′, and lasted 30 to 60 s. LV end-diastolic volume, end-systolic volume and LVEF were calculated according to the single-plane ellipsoid apical 4-chamber area-length method. Left atrial volume was calculated according to the biplane area-length method [2) was calculated using the Fick equation as follows: (VO2)/ at each activity level [Rest-stage echocardiographic images were taken before cycling . Then, echocardiographic images were obtained concurrently with breath-by-breath gas exchange measurements in a continuous manner along predefined stages of exercise: rest; unloaded cycling; AT; and peak exercise .Categorical variables were summarized as frequency and percentage. Continuous variables were described as median and IQR. In order to compare clinical, echocardiographic and metabolic parameters in patients with PAD + CAD vs. CAD or normal controls, the groups were first matched according to age, sex, chronic kidney disease, diabetes, hypertension, LVEF and extent of CAD. The McNemar test was used to compare categorical variables and the Wilcoxon test was conducted to compare continuous variables. To analyze the differences at the different stages of effort, we used the repeated-measures linear model analysis to define the within-group effect for each parameter over time, the between-group differences over time and the group by time interactions. All statistical tests were two-sided and p = 0.023 and p = 0.012) and pulmonary-function tests  were worse in the PAD + CAD group vs. the CAD or normal controls, respectively.The study group comprised 23 PAD + CAD patients. The mean age was 74.5 ± 7.1 years, 82% men, 92% had a history of smoking, the mean LVEF was 55 ± 6.3% and the mean estimated glomerular filtration rate was 63.4 ± 8.1 mL/min. The baseline characteristics of the three groups are shown in p = 0.78 and p = 0.39; p = 0.10 and p = 0.002; p = 0.032 and p = 0.0011) due to a combination of blunted stroke volume increase , impeded diastolic function  and diminished heart rate reserve , which persisted after correction for beta-blocker use   and oxygen pulse was blunted  not only due to an insufficient increase in stroke volume, but also because of a reduced oxygen extraction   and reduced mechanical efficiency , comparing PAD + CAD patients vs. CAD or controls, cardiac output was reduced (= 0.002) . ReducedUsing an elaborate protocol, we have demonstrated here that exercise limitation in symptomatic PAD is associated with a combination of central and peripheral cardiovascular factors including diastolic dysfunction, diminished heart rate reserve and limited muscle oxygen extraction.PAD is characterized by effort intolerance, which is often associated with intermittent claudication and leg pain . This inPAD patients experience a high prevalence of cardiovascular risk factors, including diabetes mellitus and hypertension ,2. FurthNotwithstanding the important effect of CO on oxygen uptake along exercise, we have shown here that peripheral oxygen extraction was reduced in PAD + CAD patients and contributed to oxygen-uptake attenuation. A signal for this limitation was demonstrated as early as the unloaded pedaling phase. The importance and the contribution of peripheral oxygen extraction to total oxygen uptake increases as CO decreases  and requ2/ΔW  is found in both normal and cardiovascular patients undergoing CPET studies. Nevertheless, a reduced ratio of ΔO2/ΔW characterizes high-risk patients  and might be caused by the presence of microvascular dysfunction, a change in the ratio of muscle fiber type or mitochondrial dysfunction. Different studies have shown that microvascular dysfunction is prevalent in PAD [The combination of exercise-induced diastolic dysfunction, blunting of cardiac output and reduced peripheral oxygen extraction also corresponds with the reduced ratio of oxygen uptake to workload in PAD + CAD patients found in our study. Usually, a constant ratio of ΔOt in PAD ,22. Furtt in PAD ,24 and mt in PAD ,26 have We have demonstrated here that PAD + CAD patients experience a high prevalence of chronotropic incompetence (CI). CI was repeatedly shown to be associated with increased morbidity and mortality in cardiovascular patients  and, in Our findings may contribute to potential therapeutic interventions in PAD. The main method of exercise training in PAD is a supervised exercise program (SEP), which has demonstrated symptomatic improvement, improved quality of life and increased walking distance in PAD . It invoOur study has several limitations. First, we used a noninvasive approach for CO and filling pressure measurements, and we calculated the anaerobic threshold according to gas exchange alone. Nevertheless, our approach enabled us to examine “real-life” patients without the bias of including only those who agree to undergo an invasive procedure. Furthermore, the use of simultaneous echocardiography enabled us to measure dynamic changes in cardiac chambers’ size and in valvular function. Second, our study group comprised PAD + CAD patients and not PAD alone. We believe, however, that the very high prevalence of CAD in PAD patients cannot be ignored, and our approach makes our findings more translational to everyday clinical practice. Third, our age- and sex-matched normal control group comprised relatively elderly patients with a low-intermediate prevalence of cardiovascular risk factors. Nevertheless, comparing our high-risk study group with a group of young and healthy controls might have damaged the validity of our findings. Fourth, despite our efforts to appropriately match the PAD + CAD group with the two control groups, these patients still had a significantly higher prevalence of smoking, a factor which might have affected our results. Nevertheless, the magnitude of difference in oxygen consumption, oxygen pulse ,41,42 anIn conclusion, using a comprehensive cardiopulmonary and stress echo test, we have demonstrated that exercise intolerance in PAD is associated with diastolic dysfunction, chronotropic incompetence and reduced peripheral oxygen extraction. Further studies are needed to establish targeted therapeutic approaches which might mitigate these limitations.


ObjectiveTo investigate the relationship between the presence of atrial tachyarrhythmia (AT) and the platelet-to-lymphocyte ratio (PLR), which is a recently described inflammatory marker.MethodsA total of 149 patients with AT and 187 healthy volunteers were included in this study. Complete blood count, serum lipids, and serum creatinine were tested, and dynamic electrocardiograms were performed routinely in all subjects. Student’s t-test, Mann-Whitney U test, logistic regression analysis, and receiver operating characteristic curve analysis were used for statistical analysis.ResultsIn the AT group, the proportions of patients with diabetes, hypertension, and coronary heart disease were higher than those in the control group. Higher blood platelet, low‐density lipoprotein, neutrophil-to-lymphocyte ratio, and PLR were detected in the AT group. In addition, haemoglobin, lymphocytes, and the fastest ventricular rate were significantly lower in the AT group. Higher PLR was identified as independently associated with the presence of AT. When a cut-off value of 119.47 was used, the sensitivity and specificity of PLR for predicting AT were 79.2% and 81.3%, respectively.ConclusionElevated PLR was associated with AT, suggesting that it might be useful in the future as an adjunct biomarker for the detection of the disease. Atrial tachyarrhythmia (AT) is an atrial arrhythmia with an atrial rate greater than 100 beats/minute. AT, characterized by abnormal, disorganized, and rapid atrial electrical activity, is a major public health problem . Atrial An increase in the count of blood cells and subtypes of leukocytes is an important cardiovascular risk factor ,4. PreviThe study design was a retrospective cross-sectional study. It was conducted in the Department of Cardiology of the Air Force Hospital from Eastern Theater of the People's Liberation Army between January 2010 and December 2020. The study participants consisted of 149 paroxysmal focal AT patients over 18 years of age, while age- and sex-matched healthy control volunteers (n = 187) were recruited to act as controls. The Helsinki Declaration principles were followed in the investigation. The study was approved by the ethics committee of the Air Force Hospital from Eastern Theater of the People's Liberation Army (0406001), and each participant signed a written informed consent before taking part in the study.The exclusion criteria were as follows: the left atrium had a diastolic diameter over 50 mm; the patient took antiarrhythmics in the past six months; the patient has been diagnosed with paroxysmal or permanent atrial fibrillation and atrial flutter; patients with the presence of permanent pacemaker, acute coronary syndrome, congenital cardiac disease, New York Heart Association (NYHA) class IV heart failure, active inflammatory and infectious diseases, severe kidney failure, severe abnormal liver function, thyroid disorder, malignancies, and alcohol consumption; and patients who were pregnant.Age, sex, history of coronary heart disease, hypertension, and diabetes were recorded for each patient. Serum low‐density lipoprotein (LDL), serum high‐density lipoprotein (HDL), serum creatinine (Cr), blood leukocytes, haemoglobin, blood platelets, and blood neutrophils were reviewed. With the help of ECGLAB dynamic electrocardiogram analysis software , the dynamic electrocardiogram characteristics were recorded. Analyses of the dynamic electrocardiograms were performed for all patients and the control population to determine the occurrence of AT, fastest ventricular rate, and slowest ventricular rate.The data were exported to SPSS version 22.0 software  for analysis. The data were analysed as follows: (1) chi-square (χ2) analysis was used to determine the relationships between categorical variables. (2) Mann-Whitney U tests were used to compare non-normally distributed variables, and independent samples t-tests were used if the dependent variables were continuous and approximated a normal distribution. (3) Univariate and multivariable logistic regression analyses were performed to identify risk factors associated with AT. A P-value of <0.05 was considered significant. (4) Receiver operating characteristic (ROC) curve analysis was used to determine the suitable PLR cut-off value for predicting AT.The study population consisted of 336 subjects (149 subjects in the AT group and 187 subjects in the control group). The baseline demographic, biochemical, and dynamic electrocardiogram characteristics of the study population are shown in Table As a result of the univariate logistic regression analysis, higher platelets , higher NLR , higher PLR , higher proportion of diabetes , hypertension , and history of coronary heart disease  were related to AT. In addition, lower lymphocyte levels , lower haemoglobin levels , and lower fastest ventricular rates  were associated with AT , haemoglobin, blood platelets, lymphocytes, NLR, PLR, and fastest ventricular rate were included in the multivariable logistic regression analysis. In the multivariate logistic regression analysis, PLR  was an independent risk factor for AT  = 0.875, 95% CI: 0.837-0.914) , a number of limitations are present. First, our study was single-centred, and the number of patients was relatively small. Second, the present study was retrospective in design and had a short duration of follow‐up. Third, we did not detect inflammatory factors such as TNF-α, IL-6, IL-8, and C-reactive protein, and the relationship between PLR and biomarkers of inflammation has not been studied. Furthermore, electrophysiological examinations were not performed on patients. Although this study has limitations, it represents one of the first evaluations of the link between PLR and AT. We confirmed that PLR is a cheap and convenient biomarker for AT.In our study, PLR was found to be an independent parameter for the presence of AT. PLR is a readily available and inexpensive parameter that can be used to predict AT. It is necessary to conduct prospective studies in different clinical settings to determine the role of this parameter in AT and other cardiovascular diseases.


We aim to develop a nomogram to predict overt hepatic encephalopathy (OHE) after transjugular intrahepatic portosystemic shunt (TIPS) in patients with portal hypertension, according to demographic/clinical indicators such as age, creatinine, blood ammonia, indocyanine green retention rate at 15 min (ICG-R15) and percentage of Portal pressure gradient (PPG) decline. In this retrospective study, 296 patients with portal hypertension who received elective TIPS in Beijing Shijitan Hospital from June 2018 to June 2020 were included. These patients were randomly divided into a training cohort (n = 207) and a validation cohort (n = 89). According to the occurrence of OHE, patients were assigned to OHE group and non-OHE group. Both univariate and multivariate analyses were performed to determine independent variables for predicting OHE after TIPS. Accordingly, receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to compare the accuracy and superiority of a novel model with conventional Child–Pugh and MELD scoring model. Age , Creatinine , Blood ammonia , ICG-R15  and Percentage decline in PPG  were independent risk factors for OHE after TIPS using multifactorial analysis. A nomogram was constructed using a well-fit calibration curve for each of these five covariates. When compared to Child–Pugh and MELD score, this new nomogram has a better predictive value . Consistently, this finding was reproduceable in validation cohort and confirmed with DCA. A unique nomogram was developed to predict OHE after TIPS in patients with PHT, with a high prediction sensitivity and specificity performance than commonly applied scoring systems. The PHT can cause common clinical manifestations such as rupture and bleeding of esophageal and gastric varices, and even intractable ascites2, making it difficult to treat. In recent years, transjugular intrahepatic portosystemic shunt (TIPS) has been widely used in PHT patients. With well-accepted advantages of minimally invasive, definite curative effects, and quick postoperative recovery, TIPS has become one of the main options for PHT treatment3. However, there are many complications after TIPS. For example, hepatic encephalopathy (HE) is a common postoperative complication after TIPS, which seriously affects the prognosis of patients and significantly increases the postoperative mortality risk7.After a long-term inflammatory response, the normal liver parenchyma is replaced by fibrotic tissues and regenerative nodules, which can subsequently progress to cirrhosis, and eventually lead to portal hypertension (PHT)8. Previous studies have suggested that the incidence of HE after TIPS can be as high as 5–35%11. Many risky factors, such as advanced age, Child–Pugh score and HE medical history can predict HE after TIPS in PHT patients12. The gradient change in portal venous pressure before and after operation is closely related to HE13. In addition, stent diameter and preoperative serum albumin level might be independent risk factors for HE in patients after TIPS14.According to clinical manifestations, HE can be divided into covert hepatic encephalopathy (CHE) and overt hepatic encephalopathy (OHE). In addition, HE may be categorized into grades 0 to 4 according to the West Haven grading criteria; of which, CHE includes grades 0 and 1, whereas OHE includes grades 2–415. Intraoperative events can affect susceptibility to HE after TIPS. Unfortunately, conventional models do not include surgery-related factors, such as stent diameter, puncture site and intraoperative pressure measurement, which cannot be used to accurately predict HE after TIPS. Recently, a prediction model related to OHE after TIPS has been developed16. Although great efforts have been made to predict OHE after TIPS, certain limitations exist due to a lack of risk factors and small sample sizes. Therefore, it is necessary to establish a more accurate prediction model for predicting the risk of OHE after TIPS in PHT patients. A novel nomogram prediction model can become an intuitive and convenient tool. Therefore, in this study, a nomogram prediction model that can more intuitively predict OHE after TIPS will be constructed to replace the conventional scoring systems. This model will help to evaluate patients at high risk of OHE and implement preventive and therapeutic measures after TIPS, thereby providing strategies for the treatment of PHT.Presently, Child–Pugh and MELD scoring systems for predicting HE after TIPS are clinically availableIn this retrospective study, 358 PHT patients who received elective TIPS at Beijing Shijitan Hospital from June 2018 to June 2020 were included. Among them, 62 patients were excluded due to incomplete data and loss to follow-up. The remaining 296 patients were randomly divided into a training cohort (n = 207) and a validation cohort (n = 89), All patients with esophagogastric variceal bleeding and refractory ascites had treatment failure after first-line treatment. This study was approved by the Institutional Review Board at Beijing Shijitan Hospital in accordance with the Declaration of Helsinki. All methods are performed in accordance with relevant guidelines and regulations.The inclusion criteria were as follows: (1) diagnosed with PHT; (2) treatment of varicose bleeding by beta-blockers or endoscopy failed; (3) patients with refractory ascites who do not respond to adequate doses of diuretics and sodium restriction; (4) with complete perioperative clinical data. The exclusion criteria were as follows: (1) diagnosed with preoperative HE; (2) previously treated with liver transplantation; (3) diagnosed with preoperative severe cardiopulmonary insufficiency or severe encephalopathy.Demographic and clinical data were collected, including age, sex, history of PHT and liver diseases. Imaging results from MRI contrast-enhanced, CT contrast-enhanced, and ultrasonography were analyzed to identify cirrhosis and ascites. TIPS perioperative tests were recorded, including complete blood count, renal function, serum electrolyte, plasma ammonia, liver function, prothrombin time, international normalized ratio and ICG-R15. The perioperative information on TIPS was recorded. In addition, the symptoms of OHE were evaluated by more than 2 experienced hepatologists according to the West-Haven criteria.17 was calculated as 11.2 × ln(INR) + 9.57 × ln + 3.78 × ln + 6.43. Three continuous factors  and two categorical variables  comprised the Child–Pugh scoring system18. According to Child–Pugh scores, patients were categorized into three grades: grade A (5–6 points), grade B (7–9 points), and grade C (10–15 points). The PHT was detected in patients with esophageal varices visible during endoscopy or with a low platelet count (100 × 109/L) related to splenomegaly 19. After excluding other possible causes of altered mental status, HE was defined as neuropsychiatric abnormalities from mild neuropsychological dysfunction to deep coma and abnormal ammonia levels20. The severity/stage of HE was evaluated. All patients were followed up at 1, 3, 6, and 12 months after TIPS, and the onset characteristics of OHE (with West-Haven score ≥ grade 2) were recorded. All OHE occurred within 3 months after TIPS, so post-TIPS OHE was defined as OHE that occurred within 3 months after TIPS. Because CHE has a relatively small effect on quality of life, it is difficult to quantify in long-term follow-up and it is difficult to include CHE in statistical analysis, so only OHE was included in statistical analysis. All patients underwent ICG-R15 testing using a dye density graph analyzer  and ICG clearance test reagent . The plasma ICG concentration was measured 15 min after injection of ICG (0.5 mg/kg).The MELD scoreTIPS was established under local anesthesia using a transjugular approach. 4-Fr pigtail catheters were placed in the right atrium, inferior vena cava (at the level of the hepatic vein), and portal vein (where the spleen and superior mesenteric vein converge) to measure the pressure before and after stent placement. For all measurements, the pressure transducer was calibrated to 0 mmHg at the level of the patient's axillary midline. Each measurement was performed three times and then averaged. PPG is the pressure difference obtained by subtracting the IVC pressure from the PV pressure.The statistical analysis was performed by SPSS 26.0  and R 4.0.3 (Institute of Statistics and Mathematics). The univariate or multivariate analysis was conducted at a test level of 0.01 or 0.05, respectively. Means of continuous variables were calculated and compared using Mann–Whitney U tests or Student's t tests. Statistically significant indicators in the univariate analysis were included in the multivariate analysis. The variables associated with OHE were assessed using logistic regression analyses. The nomogram prediction model was evaluated by establishing consistency index and evaluating calibration curve. We compared the predictive value of this new nomogram model with other predictive OHE scores. In order to determine the accuracy of this nomogram, a calibration chart with 1000 bootstrap samples was applied. DCA was used to measure clinical utility of this nomogram by calculating net benefit at different threshold probabilities.The clinical data were approved by the Ethics Committee of Beijing Shijitan Hospital Affiliated to Capital Medical University. Patients sign informed consent.A total of 296 patients including 203 males (68.58%) and 93 females 31.42%), with an average age of 51.89 years, who met the inclusion criteria were included in this study. All patients were divided into a training cohort and a validation cohort. Of which, OHE occurred in 59 patients (19.93%). These patients were diagnosed with viral hepatitis , alcoholic hepatitis , cholestatic hepatitis , or other liver diseases . Among those who underwent TIPS, 188 cases (63.51%) were confirmed with esophageal and gastric variceal bleeding, 60 cases (20.27%) developed intractable ascites, 29 cases (9.8%) suffered from esophageal and gastric variceal bleeding complicated with refractory ascites, and 19 cases (6.42%) had other liver diseases. Totally, 189 cases (63.85%) underwent puncture of left branch of portal vein, 61 cases (20.61%) underwent puncture of right branch of portal vein, while 46 cases (15.54%) underwent the puncture of portal vein bifurcation. The average decrease ratio of portal vein was 38.1% and the average decrease value of portal vein was 10.73 mmHg. The clinicopathological characteristics of these patients were summarized in Table .42%, witIn univariate models, age (p = 0.007), Child–Pugh grade (p = 0.001), ICG-R15 (p < 0.001), percentage of PPG decline (p = 0.007), percentage decline in PPG (p < 0.001), creatinine (0.004) and blood ammonia (p = 0.005) were identified as risk factors for OHE after TIPS in the training cohort Table . Then, mBased on multivariate analysis, age, ICG-R15, percentage of PPG decline, creatinine, and blood ammonia were identified as independent risk factors for OHE after TIPS. By using rms package of R software, independent factors were incorporated into a nomogram prediction model for OHE after TIPS. The expected probability of OHE after TIPS is obtained by drawing a line to the point axis to obtain the points received by the value of each variable, and the sum of these points corresponds to the total point axis , significantly higher than that of Child–Pugh score  or MELD score  Fig. A.Figure Our nomogram model was accurate in predicting OHE after TIPS in the validation cohort, with a C-index of 0.8464 (95% CI 0.7404–0.9524), higher than that of Child–Pugh score  or MELD score  Fig. B.The DCA curves indicated that our nomogram prediction model was more valuable than MELD score or Child–Pugh score Fig. A in both22. Therefore, implementation of TIPS has been restricted23, and it is very important to accurately identify PHT patients who are at risk of OHE after TIPS.With continuous improvement of hardware facilities and technical concepts, effects of TIPS on PHT therapy have becoming more and more remarkable, however, its postoperative complications remain challenging. For example, HE caused by biochemical disturbance of brain functions as a result of liver function injury and portal-systemic shunt greatly affects the quality of life27. For patients who have not experienced HE, preoperative blood ammonia level can be a predictor of HE after TIPS28. Similarly, serum creatinine was significantly associated with HE after TIPS31. The ICG-R15 retention test is a relatively non-invasive method for evaluating liver function, which is used to distinguish patients with acute and chronic liver failure32. Presently, it has been widely applied in patients with end-stage liver diseases33. Previous studies have suggested that ICG-R15 has clinical value in predicting HE after TIPS15 as well as prognosis of patients undergoing hepatectomy34. In addition, the more the portal venous pressure decreased after TIPS, the more obvious the effect of portal-systemic shunt was. The risk of postoperative rebleeding was reduced, but the risk of postoperative HE was increased13. At present, there are few studies on the percentage of PPG decline in relation to OHE after TIPS. This study has confirmed that the percentage of PPG decline is an independent risk factor for developing OHE after TIPS in PHT patients. At present, the mechanism is not clear. At the same time of the decrease of portal vein pressure, the portal vein blood flow is diverted to the systemic circulation, leading to the reduction of liver blood supply, leading to liver insufficiency and increasing the risk of postoperative HE. In addition, a large amount of ammonia-rich portal blood flow from the gastrointestinal tract directly enters the systemic circulation through the stent, causing an increase in blood ammonia and leading to the occurrence of postoperative HE.In this study, we have identified that age, creatinine, blood ammonia, ICG-R15, and percentage of PPG decline were independent risk factors for OHE after TIPS in PHT patients based on multivariate logistic regression models. Several risk factors were related to OHE after TIPS in previous studies. For example, age was associated with HE after TIPS35, and can be helpful to evaluate liver reserve function. Either Child–Pugh score or MELD score lacks indicators that can predict liver function during the operation. Therefore, there are limitations of these conventional models.Currently, Child–Pugh scoring system and MELD scoring system have certain predictive value in predicting OHE after TIPS. However, some indicators in Child–Pugh score are subjective or interrelated, so Child–Pugh score cannot accurately predict OHE after TIPS. The MELD score may predict the mortality of patients after TIPS. Presently, MELD is the most widely applied index for evaluating liver function before liver transplantationThe nomogram is an intuitive statistical tool that can provide information for decision-making in clinical practice. Therefore, we combined 5 risk factors to illustrate a combinatory value in predicting OHE after TIPS. Compared with Child–Pugh score and MELD score, our novel model had a better predictive value for OHE after TIPS. The nomogram prediction model, Child–Pugh score and MELD ROC curves were drawn to calculate C-index values. The predictive ability of our nomogram model vs. conventional models in predicting OHE after TIPS was compared. The C-index value of our novel prediction model was the highest in training cohort and validation cohort, indicating that this nomogram prediction model had a better predictive capability. In terms of validation, Bootstrap self-sampling method was used to calculate consistency index. This prediction model had good accuracy. The calibration curve fit well with the ideal curve, indicating that this nomogram prediction model had a good prediction capability for OHE after TIPS. Traditionally, nomograms have been assessed by diagnostic performance indices, and its clinical value cannot be determined. DCA can assess the benefits of various patient-preferred diagnostic tests to identify the risks of undertreatment and overtreatment, in order to facilitate decision-making. The DCA demonstrated that our nomograms provided more benefits than other models in both training and validation cohorts. Therefore, our nomograms can be applied in clinical practice. However, this study still has some limitations: (1) this study used the change value of PPG as one of the model parameters, so the model cannot predict the occurrence of OHE before TIPS; (2) as a retrospective study, there is a certain selection bias; (3) this study only carried out internal verification, but lacked external verification.In conclusion, we have demonstrated that age, creatinine, ammonia, ICG-R15, and percentage of PPG decline are independent risk factors for predicting OHE after TIPS. When TIPS is performed for PHT patients, in order to reduce the incidence of postoperative OHE, in addition to routine preoperative assessment, attentions should be paid to age and renal function. Furthermore, blood ammonia and ICG-R15 results should be assessed before the surgery. Therapeutic effects attributed to decreased portal venous pressure and the possible increased risk of HE should be balanced during the surgery. In this study, we have proposed a novel predictive nomogram for HE after TIPS. The nomogram harbors good predictive performance and would be a conventional tool to facilitate clinical decision-making.


Heart failure (HF), chronic kidney disease (CKD), and type 2 diabetes mellitus (T2DM) are common and interrelated conditions, each with a significant burden of disease. HF and kidney disease progress through pathophysiologic pathways that culminate in end-stage disease, for which T2DM is a major risk factor. Intervention within these pathways can disrupt disease processes and improve patient outcomes. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been investigated in patient populations with combinations of T2DM, CKD, and/or HF. However, until recently, the effect of these agents in patients with HF with preserved ejection fraction (HFpEF) was not well studied.The aim of this review is to summarize key information regarding the interaction between HFpEF, CKD, and T2DM and discuss the role of SGLT2 inhibition in the management of patients with comorbid HFpEF and CKD, with or without T2DM. Literature was retrieved using Boolean searches for English-language articles in PubMed and Google Scholar and included terms related to SGLT2is, HFpEF, T2DM, and CKD. The reference lists from retrieved articles were also considered. SGLT2is are efficacious and safe in treating HFpEF in patients with comorbid CKD with and without T2DM. The totality of evidence from clinical trials data suggests there are benefits in using SGLT2is across the spectrum of left ventricular ejection fractions, but there may be a potential for different renal effects in the different ejection fraction groups. Further analysis of these clinical trials has highlighted the need to obtain more accurate phenotypes for patients with HF and CKD to better determine which patients might respond to guideline-directed medical therapies, including SGLT2is.CI confidence interval, EF ejection fraction, eGFR estimated glomerular filtration rate, HF heart failure, HHF hospitalization for HF, HR hazard ratio, LVEF left ventricular ejection fraction, SGLT2i sodium-glucose cotransporter-2 inhibitor, UACR urine albumin-creatinine ratio. a Mean value, unless otherwise stated, b SGLT2i vs. placebo, c Data reanalyzed using more conventional endpoints   Heart failure (HF), chronic kidney disease (CKD), and type 2 diabetes mellitus (T2DM) are common and interrelated conditions, each conferring increased disease burden both individually and in combination . CardiovLiterature was retrieved from PubMed and Google Scholar databases using Boolean searches for terms related to SGLT2is, HFpEF, T2DM, and CKD . The reference lists from retrieved articles were also considered. Other relevant literature was obtained on the basis of the personal knowledge and experience of the authors. Additional data were obtained from the US National Institutes of Health website ClinicalTrials.gov and from websites pertaining to individual therapeutic agents of interest. The retrieved references were manually assessed by one reviewer and formed the basis for this narrative review.HF is defined as a clinical syndrome with symptoms and/or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion . Left ve2), or both  mL/min/1.73 m2) . PRESERVED-HF reported significant improvements in KCCQ and 6MWTD with dapagliflozin vs. placebo ; however2), 34% of patients had an eGFR < 30 mL/min per 1.73 m2, and 48% had urine albumin-creatinine ratio (UACR) < 300 mg/g; also, the primary renal diagnosis contained several non-diabetes–related glomerular diseases, including IgA nephropathy (12% of patients), focal segmental glomerulosclerosis (3%), and membranous nephropathy (1%)  mL/min/1.73 m2 per year), and the risk of the composite kidney outcome was similarly reduced in patients with and without CKD  [A further question is why the secondary kidney outcomes with HFpEF look different when compared with HFrEF. In a comparison of EMPEROR-Reduced and DAPA-HF , in whicctively) . HoweverDAPA-HF) . A prespnsplant) . Empaglictively) .Despite these analyses, the reason why the kidney outcomes appear to be less impressive in patients with HFpEF largely remains unknown. The comparison of EMPEROR-Reduced and DAPA-HF presents relevant points concerning the level of eGFR at trial entry, number of kidney events, and differences in definitions, but it is equally possible that the difference in kidney outcomes is simply due to chance. Furthermore, it may be erroneous to postulate that HFrEF and HFpEF consistently behave differently with respect to kidney outcomes. Data from a post hoc analysis of renal outcomes in the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with angiotensin receptor blocker (ARB) Global Outcomes in HF with Preserved Ejection Fraction trial  demonstrated a significant reduction in the prespecified kidney composite outcome  , even thAlthough SGLT2is are undoubtedly valuable in the management of HF and CKD, other drugs are also important. Finerenone is one of the standards of care in patients with DKD , 96. It Joint guidelines from the American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA 2022) now include the use of SGLT2is for patients with HFpEF   due to tThere are several limitations associated with this work. Only two databases were used in the search strategy. As the retrieved references from the searches were only assessed by one reviewer, there is a possibility of selection bias.SGLT2is have demonstrated efficacy and safety in treating HFpEF in patients with comorbid CKD, with and without T2DM. The efficacy of SGLT2is appears to be a class effect. Data from some clinical trials have led clinicians to question whether SGLT2is are effective across the spectrum of EFs in HF, and whether there may be a difference in kidney outcomes between patients with HFpEF vs. HFrEF. Further analysis of the individual trial designs and participant characteristics reveal potentially mitigating factors that may explain the relevant sets of ostensibly neutral results and highlights the need to obtain more accurate phenotypes for patients with HF and CKD  to better determine which patients might respond to different guideline-directed medical therapies. Furthermore, due to their high risk of developing HFpEF, patients with CKD may benefit from therapies such as SGLT2is, ARNis, ARBs, and MRAs even if they have not yet been diagnosed with HF.


Volume assessment, dry weight titration, and blood pressure control in pregnant kidney failure patients are often challenging, with physiological fluid accumulation in the trunk and lower limbs and an increased risk of preeclampsia. We used segmental bioimpedance in the volume management of our kidney failure patient on haemodialysis.We report a case of a female patient on maintenance haemodiafiltration with no residual kidney function for whom we used segmental bioimpedance to guide dry weight adjustment. At different gestational periods, we targeted a different extracellular to total body water ratio according to body segments. This allowed us to support her high-risk pregnancy, identify her as probably developing preeclampsia and trigger a plan for closer monitoring and delivery during the third trimester when she had rapid weight gain.Segmental bioimpedance is a practical, simple, and non-invasive test that can be performed at the dialysis unit and is useful as an adjunct decision-making tool in the management of pregnant dialysis patients.The online version contains supplementary material available at 10.1186/s12882-023-03360-6. Pregnancy is not only uncommon in patients on maintenance dialysis without residual renal function but is associated with high maternal and foetal morbidity and mortality , 2. TargWe report a female anuric haemodialysis (HD) patient who conceived naturally. After confirming pregnancy, she was converted from HD to haemodiafiltration (HDF) to improve overall solute clearances and ensure haemodynamic stability. Post-dialysis segmental bioimpedance was used to guide the clinical assessment of volume status. Our aim was to prevent fluctuations in blood pressure (BP), hypovolemia, intradialytic hypotension and hypertension and to preserve placenta perfusion. We postulated that optimal volume status with accurate titration of target weight using segmental bioimpedance, in addition to good clinical management, would allow better BP control and enable pregnancy extension to term. We used a total body and upper limb extracellular water to total body water ratio (ECW/TBW) for dry weight titration during her second and third trimester, respectively.A 25-year-old lady who had been HD dependent for 4 years due to IgA nephropathy was confirmed pregnant in 2022. Her medical history included hypertension on amlodipine, hyperparathyroidism with post-subtotal parathyroidectomy, and childhood asthma. Pre-pregnancy, her body mass index (BMI) was normal at 20.9 kg/m2 . An initBP was controlled with regular long-acting Nifedipine 60 mg twice daily and Methyldopa 250 mg daily. The erythropoietin dose was increased to achieve a target haemoglobin of 100 g/L. Her baseline transferrin saturation and ferritin were 56.5% and 738 ug/L, respectively. She was allowed an unrestricted, high protein diet supplemented with folic acid, and prenatal vitamins [Weekly segmental bioimpedance was measured with the InBody S10  in a standardized manner 20 min after completing the dialysis session, after allowing time for re-equilibration and blood test results were checked to ensure optimum volume management and guide dialysis target weight setting throughout pregnancy . Pre-dialysis measurements differ from post-dialysis measurements, as patients are usually volume overloaded in the pre-dialysis state hence, bioimpedance measurements overestimate muscle mass and under estimate fat mass, due to the difference in the water content between muscle (≈ 90% water and fat tissue < 10%) [An ultrasound scan at 18 weeks demonstrated an absence of the right umbilical artery, with a further scan at 21 weeks demonstrating bilateral increased uterine artery resistance with unilateral notching of the right uterine artery Doppler. Her dialysis sessions were lengthened to 6.5 hour, Qb was increased to 270 mL/min, and convective volume to 60 L at 20 weeks. With this change, she remained well with good BP control. The standard weekly Kt/V measured 6.71 to 7.5. At 21 weeks, she tested positive for COVID-19 infection, and was hospitalized for one week. She lost weight during her hospitalization and was not able to tolerate oral nutritional supplementation. We observed a reduction in total body ECW/TBW post COVID-19 admission from 0.391 to 22 weeks gestation to 0.379 at 26 weeks gestation  and lower limb (0.384–0.409) compared to non-access upper limb (0.372–0.389), as expected. Her body fat mass increased during this period from 18.9 to 23.3 kg while skeletal muscle mass remained stable. Her weight gain ranged from 0.7 to 3.2 kg/ week, with a total weight gain of 12.4 kg. Data from serial bioimpedance measurements provided additional information to account for the increasing body weight, differentiating it from overhydration. Her intradialytic hypertension improved each time with up-titration of target weight guided by bioimpedance but there was also a suspicion that this could represent early signs of pre-eclampsia. Foetal size was below average, but growth velocity was sustained throughout the third trimester  and is thought to be driven by a placental disorder that leads to maternal endothelial dysfunction. While biomarkers, including soluble fms-like tyrosine kinase (sFlt-1) and placenta growth factor, may aid in predicting preeclampsia, these tests are not readily available and have a lower predictive performance in kidney failure patients . Also, tCross-sectional studies have compared bioimpedance measurements of ECW and ICW with those of gold standard isotope dilution methods, and bioimpedance spectroscopy was not found to be superior to single frequency (50 Hz) measurements in dialysis patients . We usedSegmental bioimpedance allowed a more accurate adjustment of the dry target, given the accumulation of amniotic fluid in the trunk and fluid retention in the legs with advancing gestational age. Specific to pregnancy, bioimpedance has been reported to be able to distinguish patients developing preeclampsia from those having merely pregnancy-induced hypertension and to identify those at risk of having small for gestational age foetuses at an earlier gestational stage . BioimpePregnant dialysis patients are at increased risk of developing preeclampsia. Its diagnosis and the decision and timing of delivery are often challenging, striking a balance between the risk of worsening preeclampsia and its associated morbidity against the risk of foetal prematurity. Segmental bioimpedance in our patient showed rapid weight gain from 28 weeks onwards and provided us with information that was important in our discussion with the obstetric team on the anticipated timing of delivery and administration of dexamethasone. Segmental bioimpedance is a simple, fast, and non-invasive test that can help better support pregnancy and identify high risk patients.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2


Hypertension (HT) remains the leading cause of death worldwide. In Brazil it is estimated that 35% of the adult population has HT and that about 20% of these have blood pressure values within the targets recommended for the reduction of cardiovascular risk. There are some data that point to different control rates in patients treated by cardiologists in public and private referral center and this is an important point to be investigated and discussed.To compare sociodemographic characteristics, body mass index (BMI), antihypertensive (AH) drugs, blood pressure (BP) and control rate in public (PURC) and private (PRRC) referral centers.χ2 tests or unpaired t-tests were performed. A significance level of p < 0.05 was considered.A cross-sectional multicenter study that analyzed data from hypertensive patients assisted by the PURC (one in Midwest Region and other in Northeast region) and PRRC (same distribution). Variables analyzed: sex, age, BMI, classes, number of AH used and mean values of systolic and diastolic BP by office measurement and home blood pressure measurement (HBPM). Uncontrolled hypertension (HT) phenotypes and BP control rates were assessed. Descriptive statistics and p < 0.001) and overweight in PRRC (p < 0.001). The mean AH used was 2.9 ± 1.5 for PURC and 1.4 ± 0.7 for PRRC (p < 0.001). Mean systolic and diastolic BP values were higher in PURC as were rates of uncontrolled HT of 67.8% and 47.6% (p < 0.001) by office measurement and 60.4% and 35.3% (p < 0.001) by HBPM in PURC and PRRC, respectively.A predominantly female (58.9%) sample of 2.956 patients and a higher prevalence of obesity in PURC (Patients with HT had a higher prevalence of obesity in the PURC and used almost twice as many AH drugs. BP control rates are worse in the PURC, on average 15.3 mmHg and 12.1 mmHg higher than in the PRRC by office measurement. Hypertension (HT) remains the leading cause of death worldwide. Despite this, it remains underdiagnosed and undertreated . In BrazHowever, when we evaluate the rates of HT control in patients treated by cardiologists and in private services, the values found are better than those described in the databases of patients assisted in the Unified Health System (SUS) and can reach 60.6% –6.Further, it is well established that both diagnosis and assessment of HT control by BP monitoring methods are more accurate than office measurement and should be performed whenever possible , 7, 8.Given this scenario this study aimed to compare BP values and BP control among hypertensive patients followed up in public referral center (PURC) and private referral centers (PRRC), located in two regions of Brazil (Midwest and Northest) under the coordination of the same medical team and following the same treatment protocols established by the Brazilian Guidelines on Hypertension .telemrpa.com.br) between the years 2017 and 2021. The BP values were recorded and stored in the equipment memory and were then included in the TeleMRPA® platform, a telemedicine tool for providing remote reports.A cross-sectional multicenter study that analyzed data from patients with HT assisted by the PURC and PRRC obtained from an online platform (Participants needed to be 18 years of age with a diagnosis of HT and in the use of antihypertensive (AH) drugs to be included. All patients with these criteria were included. The sample was calculated considering a prevalence of HT in Brazil of 32.3%  and comprised the following data: age, sex, body mass index (BMI) using Quetelet's formula , classesNutritional status was classified as overweight (yes or no), obesity (yes or no). and overweight (yes or no). Overweight was considered as those classified as overweight and obese I, II or III .OMRON brand automatic digital devices were used for BP measurements. The HT was standardized through the protocols of the Brazilian Guidelines for Ambulatory Blood Pressure Monitoring and Guidelines for Residential Monitoring of Blood Pressure 2018 . Six meaContinuous variables with normal distribution were presented as mean and standard deviation while those without normal distribution were presented as median . Categorical variables were presented as proportions.Student'st-test for continuous variables with normal distribution, Mann-Whitney test for continuous variables without normal distribution and χ2 for categorical variables. A-value of p < 0.05 was considered statistically significant. Analyses were performed using STATA version 14 software.To compare the variables between the groups studied the following statistical tests were used: A total of 2.956 participants were evaluated, of which 1.789 (60.5%) and 1.167 (39.5%) were from the PRRC and PURC groups respectively with no age difference. The frequency of males was higher in the private service .As for nutritional status, only 21.7% of the sample was not overweight with a higher prevalence of obesity in the PURC compared to the PRRC.Regarding antihypertensive drugs, the use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) was similar in both groups. However, all other classes have a higher frequency of use in patients followed up in the public service. The mean number of antihypertensives used was 2.0 ± 1.3 for the total sample; 1.4 ± 0.7 for PRRC and 2.9 ± 1.5 for PURC (p < 0.001) .All mean blood pressure values, both from office measurements and HBPM in the PURC and PRRC are described in Regarding the possible phenotypes of uncontrolled BP in treated patients with HT, the frequency of sustained hypertension (SH), when both office BP and HBPM are above the recommended targets, was higher in the SRPU. However, masked hypertension (MH) was more frequent in PRRC .Furthermore, we evaluated all 904 patients (30.6%) who were using 3 or more classes of antihypertensive drugs in combination. Further, we found this subgroup had a higher prevalence of uncontrolled HT in the PURC .The sample evaluated consisted of people with HT with an average age of just under 60 years and an overweight average body mass index. We observed a higher prevalence of females in the total sample, with an even higher prevalence in the PURC. This characteristic of higher frequency of medical care by females has already been described in other publications and denotes the lack of attention to men's health concerning HT , 11.Another important aspect observed in the sample was the higher overweight prevalence in the PRRC (43.0%) and obesity in the PURC (42%). Such characteristics may denote a poorer quality diet and an increased association with comorbidities or severity of hypertensive disease in patients in the public service because it is known that increased BMI and abdominal circumference are risk factors for both increased BP and major cardiovascular diseases –14. MorePURC patients used a greater number of antihypertensive medications. Moreover, except for the classes that block the renin-angiotensin-aldosterone system (ACEI or ARB), the other classes were used more frequently in the PURC. As for antihypertensives available for use in the basic health network in our country, most of them have short half-lives and we do not have fixed combinations in a single pill. This reality leads to the need for the use of a greater number of drugs, pills and daily doses. This is known to be associated with lower adherence to treatment and resulting worsening in BP control , 17, 18.Despite the greater number of AH used in PURC, the mean SBP and DBP values, whether measured in the office or by HBPM remained significantly higher than in PRRC. The consequence of a higher number of uncontrolled patients is an increase in the incidence of major associated CV outcomes. Effectively improving the control of HT means dramatically reducing the incidence of stroke, acute myocardial infarction, heart failure and chronic kidney disease –21.p < 0.001).When we evaluated the possible phenotypes of uncontrolled HT, we found a higher prevalence of SH in the PURC. This phenotype is the one with the worst prognosis relating to cardiovascular outcomes in hypertensive patients since it denotes a lack of BP control in both office measurements and HBPM . This asWhen evaluating the subgroup using three or more AH drugs, we found higher levels of patients off target by both the office measure and HBPM which was to be expected and similar to the total sample, those followed up in the PURC had worse control rates than the PRRC group.This study has some limitations since we have not evaluated socio economic level and adhesion with specific tools, however, by evaluating a population of more than 3,000 hypertensive patients using public and private reference centers under the same coordination, we believe it is possible to evaluate with less bias the aspects related to drug use in both scenarios and the impact on BP control. Furthermore, the information obtained both by the office measurement and by the HBPM allows greater accuracy in the evaluation of the recommended goals.It was possible to observe that patients followed up in public referral centers have a higher prevalence of obesity and use more than double the number of antihypertensive drugs than private services.The blood pressure control rates assessed by both office measurement and HBPM are always worse in the PURC and on average 15.3 mmHg and 12.1 mmHg higher than in the PRRC for SBP and DBP, respectively, in the office measurements.The poorer control of HT is associated with a higher incidence of the main cardiovascular outcomes. Therefore, there is an urgent need to reassess strategies so that, in the end, we can decrease the disparities between public and private services and increase our hypertensive population's cardiovascular protection.


Pharmaceutical care has the potential to improve hypertension control rates in young and middle-aged patients. Due the COVID-19 epidemic, standard intervention methods may not be applicable. We propose establishing an internet-based pharmaceutical care (IPC) route to improve blood pressure control in young and middle-aged patients with hypertension. An evaluation method based on Principal Component Analysis (PCA) and Orthogonal Partial Least-Discriminant Analysis (OPLS-DA) was established to evaluate the effect of the IPC method.1) Internet-based Pharmaceutical care (IPC) was provided by pharmacists mainly using Wechat software for one year after enrollment; 2) PCA and OPLS-DA were applied to analyze questionnaire reliability and data variability; 3) Markov cohort was used to evaluate the IPC effect.Ninety-seven young and middle-aged patients were enrolled. 96 patients received the IPC. 1) The blood pressure control rate increased to 71.88% after IPC in 96 patients. 2) After conducting PCA and OPLS-DA analysis, 10 questions in the questionnaire were significantly improved after the IPC. 3) Markov cohort results showed that patient survival after 28 cycles was 18.62 years and the quality-adjusted life year (QALY) was extended by 5.40 years. The cumulative cost-effectiveness ratio was ¥87.10 per QALY.The IPC method could significantly improve the blood pressure control rate of patients. The questionnaire analysis method based on PCA and OPLS-DA is an effective method to evaluate the effect of the IPC method. The Markov cohort showed that the IPC had an effect on blood pressure control rate changes. Patients had a strong willingness to pay for IPC.The online version contains supplementary material available at 10.1186/s12955-023-02168-0. Long-term treatment of hypertension is widely recognized as a significant public health challenge worldwide due to its high incidence of associated complications , 2. In CP < 0.001) [Effective pharmaceutical care, including medication and lifestyle, might be the main measure for controlling blood pressure. A study showed that the control rate was effectively improved (46.9%) after 3 months of pharmacist intervention . A meta-< 0.001) . However< 0.001) . The pan< 0.001) . TherefoThe objective of this study was to achieve sustained and stable control of blood pressure below 120 mmHg through the implementation of IPC intervention. The evaluation of the effect of pharmaceutical care mainly relies on patients' subjective scores of pharmacists, and the verification of objective indicators is lacking. In this study, patients' blood pressure and compliance questionnaires were used to evaluate patients' blood pressure control. The Markov cohort was used to objectively evaluate pharmaceutical care. Our research group has examined the principal component analysis (PCA) and orthogonal partial least-discriminant analysis (OPLS-DA) for the prognosis analysis of inpatients , 18. In The Institutional Review Board has approved this study. All patients have signed an informed consent form. From March 1,2021 to February 28, 2022, 97 patients with hypertension were enrolled at Fuwai Yunnan Cardiovascular Hospital in Kunming, China. The enrolled patients had not previously participated in any other national or community health support program related to their hypertensive health issues. Initially, all patients who met the criteria were willing to participate in the program. The duration of the treatment phase was one year. The inclusion criteria, according to the enrollment criteria, were as follows: 1) patients who were young and middle-aged (18 ~ 65 years old); 2) essential hypertension based on the Chinese Hypertension Guidelines for 2020 [The IPC, based on the PICO model , was primarily conducted by pharmacists. This patient-centred pharmaceutical care was divided into four key steps. Firstly, problems were identified through questionnaires. Secondly, the pharmacist made timely interventions. Thirdly, blood pressure and questionnaire results were compared before and after the intervention. Finally, the effect of the pharmacist’s intervention was evaluated. This patient-centered pharmaceutical care consisted of two parts: health education and questionnaire evaluation, as illustrated in Fig. The patients completed the first questionnaire upon enrollment as the basic data. At the same time, they were added to a pharmacist contact group on the WeChat app, where they could receive advice if they encountered any issues with their medications. The basic knowledge of hypertension management methods was announced twice a month to the contact group. Additionally, two online sessions were conducted with guest physicians over the course of a year to discuss life stress reduction, smoking cessation, and alcohol consumption limitation. Electronic health materials were distributed 22 times, and health management materials were posted once. After the intervention, patients were asked to complete the questionnaire three times (every three months) to evaluate the effectiveness of the IPC. The index for controlling blood pressure was defined as having a systolic blood pressure ≤ 120 and a diastolic blood pressure ≤ 90, measured at home during nighttime . The tarPCA of Simca 14.1 software  was used to analyze questionnaire data and investigate its reliability. OPLS-DA was used to maximize the separation effect before and after IPC. Variables with importance in projection values > 0.5 or < -0.5 were selected in the S-plot.Hypertensive disease was defined by three Markov cohort states: poorly controlled blood pressure, well controlled blood pressure, and death Fig. . The MarAccording to the criteria, 97 young and middle-aged hypertensive patients were enrolled, Of which 96 were followed up (with one patient dropping out during the third questionnaire). The dropout rate was 1% and was due to lack of contact. The characteristics of the 96 patients are presented in Table P > 0.05)  of 13 mmHg on average and diastolic blood pressure (DBP) of 7 mmHg on average. After 6 months of intervention, blood pressure control remained stable  1.95 ± 2.55 min (after pharmacist training); 2) 6.25 ± 3.19 min; 3) 5.03 ± 2.66 min; 4) 4.20 ± 3.07 min.Simca 14.1 software was used to analyze the reliability of PCA questionnaire data. The results of the first, third, and fourth questionnaires all fell within 99% confidence intervals. The probability that the results of the second questionnaire fell outside the 99% confidence interval  .There were no significant differences in questionnaire scores between the two adjacent groups. There was a difference before and after the intervention (05) Fig. . The effThe S-plot of the OPLS-DA analysis showed a clear sesparating trend for the distribution of data for the two groups before and after the intervention. The VIP value of systolic blood pressure in the patient was < -0.5, indicating that the patient's systolic blood pressure decreased significantly. A total of 10 questions in the questionnaire had VIP values > 0.5, indicating that the scores improved significantly after the intervention Fig. .Fig. 4AnThe natural mortality rate in China in 2021 was 7.18‰. The incidence and control rates of hypertension were 27.50% and 11.00%, respectively –28. The The average age of the enrolled patients was 46.63 years old as the initial value of the Markov cohort. Patient survival without intervention was 13.22 years. After one year of pharmacist intervention, patient survival increased by 18.62 years, and the quality adjusted life year (QALY) increased by 5.40 years. The results of the Markov cohort showed that after 28 cycles (28 years), the probability of uncontrolled hypertension was 11.92%, the probability of controlled hypertension was 31.06%, and the probability of death was 57.02%. The results of the Markov cohort for 96 patients are presented in Table This study set one-time per capita GDP as the threshold value for willingness-to-pay (WTP). According to official data, the per capita GDP in 2021 was ¥57,700 in Yunnan, southwest China . The totThe probability of achieving blood pressure control in the study was determined using field data. Since the follow-up time was only one year, the blood pressure control rate was not very accurate. Therefore, a single factor sensitivity analysis was performed for the probability of conversion. With a 10% reduction in the control rate, the deaths rose to 57 after 28 years in the sensitivity analysis of the Markov cohort wherein the control rate was the influencing factor. As the control rate rose, the deaths decreased to 52. Effective interventions could significantly reduce the mortality of patients.The cost of IPC was ¥7,470. The implications of changes in cost (± 20%) were investigated. The cumulative cost for the 28 cycles of the Markov cohort ranged from ¥378.85 to ¥561.90. This value is well below the per capita GDP of ¥57,700. This result indicates that patients have a higher willingness to pay for IPC.All three methods were initially used to evaluate the IPC. For the first time, PCA analysis in combination with OPLS-DA analysis was applied to evaluate questionnaires, demonstrating its ability to quickly filter data, and identify reliable questionnaires. Additionally, the advantages of this method, which enable rapid screening of reliable questionnaires and searching for differences between pre- and post-intervention questionnaires, become more important as the number of patients increases.The application of the Markov cohort in economic comparisons of treatment regimens is widely recognized –33. ThisIn this study, young and middle-aged patients used Wechat software to complete the questionnaire, a cost-effective and convenient software that takes advantage of the cell phone and Internet-dependent nature of the young and middle-aged population. Previous studies have suggested that patients' high workloads and busy lifestyles are the main causes of noncompliance , which was confirmed in this study. The blood pressure was higher during the fourth visit than at enrollment in five patients. The field report of elephone follow-up revealed that three patients had stopped taking their medication on their own, but after receiving timely education, they are now taking it normally. One patient responded directly to the pharmacist that he was working a lot of overtime during this time of the year and had a bad time off. One patient had unstable blood pressure and did not consult a physician in time . PatientWith the advent of COVID-19, many countries have conducted similar studies on Internet-based mobile health services . These mData was collected from a questionnaire of 96 patients conducted by two pharmacists with each pharmacist's management time being limited. The results suggest that there might be an inverse relationship between the number of patients and IPC costs at this stage of the study. To further study, additional patients could be enrolled. However, we were also concerned that the quality of the intervention might decline as the number of patients increases. Therefore, the optimal ratio between pharmacists and patients needs further study.The one-year blood pressure control rate was 71.88%, which was higher than the expected target (70.00%), suggesting that the IPC method was effective. The compliance of hypertensive patients improved after one-year intervention, and the QALYs increased by 5.40 years. A meta-analysis of 2877 patients who received the intervention for 6.38 ± 3.11 months showed a compliance rate of 75.69 ± 14.07% in patients who received the intervention offline and online (78.23 ± 17.71%) . InteresThe names, dose, and dosage regimens of the antihypertensive medications administered to the patients in the intervention were considered important confounders (variables) that could affect the study's outcome . As the The IPC method can significantly improve the blood pressure control rate of patients. In the Markov cohort, the effect of IPC could be objectively assessed by changes in blood pressure control rates. Patients had a strong willingness to pay for IPC. Method innovation: 1) questionnaire analysis method relying on PCA and OPLS-DA is an effective method to evaluate the effect of IPC method; 2) the Markov cohort evaluated the effect of pharmaceutical care.Additional file 1: Supplement figure 1. The principal component analysis (PCA) results of the first (A), second (B), third (C), and fourth (D) questionnaires.Additional file 2: Supplement figure 2. Hotelling’s T2 range column plot of the second questionnaires (A) and contribution plot (B) of NO.1, NO.35, NO.62, and NO.70 patients.


Sedation is sometimes necessary in veterinary practice to perform different medical procedures, such as echocardiography or radiography, due to uncooperative or aggressive patients. In patients with cardiovascular disease, anxiety needs to be reduced; however, hemodynamic conditions have to be preserved, so it is advisable to avoid sedatives such as alpha-2 agonists or phenothiazine, due to their cardiovascular side effects. Many studies support the cardiovascular stability obtained by the administration of alfaxalone, alone or in combination, in dogs. Butorphanol is a synthetic opioid characterized by minimal cardiovascular effects, making it an ideal drug for sedation protocols. We aimed to evaluate the hemodynamic impact of the administration of intramuscular alfaxalone and butorphanol in healthy dogs. The evaluation involved assessing the degree of sedation and the effects of the sedation on cardiorespiratory, echocardiographic, radiographic and electrocardiographic parameters at baseline and 30 min after the administration of sedation. Although statistically significant changes were observed in some of the studied parameters, no clinical alterations were found 30 min after drug administration. The results showed that alfaxalone and butorphanol at the doses used in this study provided moderate sedation for performing diagnostic procedures, and they caused mild hemodynamic and respiratory changes.2 and partial pressure of O2 and CO2 were found. Echocardiographic variables, including end-diastolic volume, left ventricular diameter in diastole, aortic and pulmonic flow, diastolic transmitral flow and left atrial/aortic ratio, and electrocardiography parameters, including PQ interval and QT interval, showed statistically significant changes. In conclusion, the intramuscular administration of alfaxalone and butorphanol to healthy dogs produced moderate sedation with mild cardiorespiratory, echocardiographic and electrocardiographic changes, without alterations in cardiac size on radiographic images.The quality of sedation and changes in cardiorespiratory variables after the intramuscular administration of alfaxalone and butorphanol in Spanish greyhound dogs were evaluated. Twenty-one adult dogs were included. The dogs received alfaxalone (2 mg/kg) and butorphanol (0.2 mg/kg) intramuscularly. Sedation scoring, cardiorespiratory parameters , echocardiography, thoracic radiography and electrocardiography were performed before sedation and 30 min after drug administration. Moderate sedation was observed, and side effects, such as tremors, nystagmus and auditory hyperesthesia, were noticed. Statistically significant changes in heart rate, invasive blood pressure, pH, arterial saturation of O Sedation is used in daily clinical practice to perform different minor medical procedures, to conduct diagnostic imaging studies and to manage aggressive, nervous or excited patients. In patients with cardiovascular disease, the preservation of the hemodynamic condition is important for diagnostic procedures that aim to investigate cardiovascular function. Moreover, it is recommended to avoid stress and excessive manipulation in these patients, so intramuscular sedation is useful when the patients cannot be handled awake to perform the diagnostic procedure. The sedative protocol used for this purpose should ideally reduce anxiety, provide immobilization and produce minimal or no cardiovascular changes . In dailAlfaxalone is a synthetic neuroactive steroid that produces anesthesia through an interaction with the gamma aminobutyric acid (GABA)A receptor within the central nervous system , and itsButorphanol is a kappa receptor agonist and a mu receptor antagonist that causes dose-dependent sedation with minimal cardiopulmonary depression . SeveralThe objective of this study was to evaluate the sedation quality and the effects on cardiorespiratory, echocardiographic, electrocardiographic and radiographic parameters of the intramuscular administration of alfaxalone in combination with butorphanol in healthy Spanish greyhound dogs. Our hypothesis is that the intramuscular combination of these drugs will provide a good quality of sedation and minimal variations in the studied parameters.This observational, prospective and clinical study was performed at the Veterinary Teaching Hospital, University of Córdoba. It was approved by the Ethical Committee for Animal Welfare at the Teaching Hospital of the University of Córdoba (CEBAHCV 47/2020). All procedures were conducted in compliance with the ethical principles of good practice in animal experimentation and with the previous informed consent of the owners. Twenty-one client-owned, adult, sexually intact dogs  scheduled to undergo neutering at the Veterinary Teaching Hospital of the University of Cordoba were enrolled in the study. All dogs were greyhounds (Spanish greyhound), and the inclusion criteria required the dogs to be aged >1 year and be in good health, according to their history and the results of a complete physical examination, preoperative serum biochemistry and hematologic analyses. Dogs with evidence of cardiopulmonary dysfunction on clinical, electrocardiographic or echocardiographic examination and animals currently on medication were excluded.®, B Braun GmbH, Melsungen, Germany) was placed into the pedal artery 20 min after the application of topical anesthesia (EMLA 5% cream). Prior to taking the baseline (BL) measurements, all dogs were allowed to acclimate to the room. The dogs were placed in right lateral recumbency. Their heart rate (HR), respiratory rate (RR), temperature (Tº) and invasive arterial blood pressure (IBP) were recorded from the pedal artery. An arterial blood sample was taken, and blood gases were measured. A thoracic right lateral view radiograph was taken, and a six-lead ECG and standard echocardiography were performed.Animals were admitted two days before surgery. On the morning of the study, a 20-gauge cannula  and 2 mg/kg of alfaxalone , intramuscularly in the hind limb. Dogs were kept in a quiet room and observed continuously. Twenty minutes after baseline measurements were taken, each dog was sedated via the administration of 0.2 mg/kg of butorphanol  were recorded. The quality of sedation was scored at BL and PS using 3 different scales by evaluation of spontaneous posture, palpebral reflexes, position of the eye globes, jaw tone, response to sound, resistance to physical restraint in lateral recumbency and response to pain ,19,27. S2), oxygen saturation (StO2) and partial pressure of carbon dioxide (PaCO2) values were registered after correction for rectal temperature.The recorded cardiorespiratory parameters included HR, determined by cardiac auscultation; RR, determined by visualization of thoracic movements; and rectal temperature measured using a digital thermometer. In addition, the values of IBP, systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and mean arterial pressure (MAP) were obtained from an arterial catheter that was connected to a pressure transducer. The transducer was previously zeroed, positioned at the xiphoid cartilage level and connected to a multi-parameter monitor . Arterial blood samples were collected from the pedal arterial catheter using a one-milliliter heparinized syringe. Samples were analyzed using a blood gas analyzer  immediately after sampling. The pH, partial pressure of arterial oxygen  with frequency selection based on the patient’s size. During the acquisition of right parasternal long- and short-axis views, subxiphoid view and left parasternal long view, an electrocardiogram was recorded. M-mode, two-dimensional (2D), and pulsed-wave (PW) Doppler were used for quantitative analysis of the heart. M-mode measurements of the following parameters were registered: the left ventricular diameter in diastole (LVIDd), left ventricular diameter in systole (LVIDs), left ventricular shortening fraction (FS) (FS% = [(LVIDd – LVIDs) / LVIDs] × 100), left atrial diameter in early systole (LA), aortic diameter in diastole (Ao) and left atrial/aortic ratio (LA/Ao). Using the 2D mode, the end-systolic volume (ESV) and end-diastolic volume (EDV) were measured using the modified Simpson method, and the ejection fraction (EF) (EF% = [(EDV – ESV) / EDV] × 100) was calculated. The PW Doppler was used to measure the aortic flow (Ao Vmax), pulmonic flow (PA Vmax), early rapid ventricular filling wave (E-wave), late filling from atrial contraction (A-wave) and E-wave/A-wave ratio (E/A).Vertebral Heart Score (VHS) determination was performed using the thoracic right lateral view radiograph, acquired at the peak of inspiration. The long and short axes of the heart were transposed onto the vertebral column and recorded as the number of vertebrae, starting at the cranial edge of T4.A 6-lead ECG was recorded using computerized electrocardiography , and the PR interval and corrected QT interval were determined using a logarithmic formula (QTc = 600 × log QT/RR log).A required sample size of 20 animals was determined . The sample size was calculated based on the detection of a variation in mean blood pressure of 10 mmHg, assuming a mean value of 90 mmHg and a standard deviation of 15 mmHg, a power of 80% and an alpha error of 0.05.® SPSS® Statistics for Windows, version 25.0, IBM Co., Armonk, NY, USA). The normality of the data distribution was assessed using a Shapiro–Wilk test. A paired-sample t-test was performed to detect differences between baseline and post-sedation values for each registered parameter. Ordinal data were analyzed using the Wilcoxon signed-rank test. Normal variables were reported as mean ± SD, with ordinal variables as median (P25–P75) and nominal variables as percentage. Statistical significance was set at p ˂ 0.05.Statistical analysis was performed using IBM Statistics SPSS v25 (IBMp = 0.001), B  and C  scales. Adverse events were registered after sedation. Tremors were detected in 6/21 (28.6%), nystagmus in 5/21 (23.8%) and auditory hyperesthesia was detected in 4/21 (19%) dogs. Sedation quality at baseline was scored as 0 in all dogs. Thirty minutes after the administration of sedation, the median score value for Scale A was 2 (1.5–2), which was equivalent to moderate sedation. For Scale B, the median value was 9 (7.5–11), and for Scale C, the median value was 3 (3–4), equivalent to moderate sedation. For this reason, significant differences in sedation were detected with the A  and butorphanol (0.2 mg/kg) to healthy Spanish greyhound dogs produced adequate sedation to permit cardiovascular examination with mild cardiovascular depression, mild echocardiographic measurement alterations and no alterations in cardiac size on X-ray images. However, previously described side effects, with tremors being the most frequent, were detected. Moreover, this combination must be used with caution in patients with prolongation of the QT interval due to the possible arrhythmogenic potential.