Bronchial Thermoplasty (BT) is an endoscopic treatment for severe asthma using radiofrequency energy to target airway remodeling including smooth muscle. The correlation of pulmonary function tests and BT response are largely unknown. Forced Oscillation Technique (FOT) is an effort-independent technique to assess respiratory resistance (Rrs) by using pressure oscillations including small airways.To investigate the effect of BT on pulmonary function, assessed by spirometry, bodyplethysmography and FOT and explore associations between pulmonary function parameters and BT treatment response.Severe asthma patients recruited to the TASMA trial were analyzed in this observational cohort study. Spirometry, bodyplethysmography and FOT measurements were performed before and 6 months after BT. Asthma questionnaires (AQLQ/ACQ-6) were used to assess treatment response.p = 0.004 and p = 0.02 respectively). Pulmonary function parameters remained stable. Improvement in FEV1 correlated with AQLQ change (r = 0.45 p = 0.03). Lower respiratory resistance (Rrs) at baseline (both 5 Hz and 19 Hz) significantly correlated to AQLQ improvement ). Borderline significant correlations with ACQ improvement were found (r = 0.30 p = 0.16 for 5 Hz and r = 0.41 p = 0.05 for 19 Hz).Twenty-four patients were analyzed. AQLQ and ACQ improved significantly 6 months after BT (AQLQ 4.15 (±0.96) to 4.90 (±1.14) and ACQ 2.64 (±0.60) to 2.11 (±1.04), 1 correlated with asthma questionnaires improvement including AQLQ. Lower FOT-measured respiratory resistance at baseline was associated with favorable BT response, which might reflect targeting of larger airways with BT.Pulmonary function remained stable after BT. Improvement in FEVNCT02225392; Registered 26 August 2014.ClinicalTrials.gov Identifier:  Bronchial Thermoplasty (BT) is an endoscopic treatment for patients with severe asthma. It uses radiofrequency energy delivered to the medium and larger airways to reduce airway smooth muscle (ASM) mass –5. Sever1) up to 5 years after BT with only the RISA trial showing an improvement in FEV1 6 months after BT [Pulmonary function measurements before and after BT have shown various results and correlations with treatment response have not been explored comprehensively. The large clinical trials and long term follow up studies thereafter showed a stable one-second forced expiratory volume (FEVafter BT .Forced Oscillation Technique (FOT) is an effort-independent technique using various pressure oscillations to assess the relation between flow and pressure in the respiratory system . It has This study hypothesized that the BT-induced reduction of ASM in the larger airways influences the mechanical properties of the asthmatic airways. The aims of this trial are (1) to assess the effect of BT on pulmonary function parameters as assessed by spirometry, bodyplethysmography-determined airway resistance and FOT; (2) to evaluate whether pulmonary function parameters are related to BT response.trials.gov NCT02225392) [Patients fulfilling the World Health Organization (WHO) and Innovative Medicine Initiative (IMI) criteria for severe refractory asthma and scheduled for BT and pulmonary function tests including FOT between December 2014 and September 2018 were included  , 14. EthPatients were treated with BT according to current guidelines using the Alair System  –17 and uAll pulmonary function tests were performed in the morning and conducted by experienced staff according to ERS/ATS standards using Jaeger Masterlab software . The measurements were performed during two visits: one visit before and one visit 6 months after treatment. During the visits, short acting bronchodilators were stopped for at least 6 hours. Long acting beta agonists (LABA) were continued. Spirometry, bodyplethysmography and FOT measurements were performed both before and after administration of 400 μg salbutamol. FOT was performed in an upright position with the Resmon Pro device using a pseudorandom noise signal . The subjects received a nose-clip and patients were instructed to support their cheeks with their hands while breathing tidal for 3 min. This measurement was performed twice and the average was used in the analysis.The main outcome parameter of this study was the change in pulmonary function assessed by spirometry, bodyplethysmography and FOT. Other outcome parameters were the correlations between baseline and change in pulmonary function parameters and baseline and change in asthma quality of life questionnaires (AQLQ) and asthma control (ACQ-6) , 20. ChaP-values were two sided and a statistical significance was set at p < 0.05.GraphPad Prism version 5.01  was used for the analysis. Grouped data were reported as mean with standard deviation or median with interquartile ranges, as appropriate. Within group analyses were performed with paired t-tests or Wilcoxon signed rank tests. Correlation analyses were performed with Spearman’s rho coefficient. p = 0.004) and ACQ questionnaires improved from 2.64 (±0.60) to 2.11 (±1.04) (p = 0.02).BT and pulmonary function tests including FOT were performed in 26 patients. Two patients were excluded from analyses due to lost to follow up at the 6 months visit. Baseline characteristics of the included 24 patients are shown in Table 1 did not significantly change after BT. FVC  was slightly increased after BT, with a stable FEV1 resulting in a reciprocal decrease in FEV1/FVC. Additionally, a minimal increase in post bronchodilator airway resistance was found  kPa*s/L versus after BT 0.23  kPa*s/L (p < 0.05)).The effect of BT on spirometry and bodyplethysmography parameters are shown in Table Total group analyses of FOT measurements did not show a change in respiratory resistance (Rrs) and reactance (Xrs) after BT for both 5 Hz and 19 Hz Table .Table 3Associations between asthma questionnaires and pulmonary function parameters were explored.1 reversibility (for AQLQ r = 0.42 p = 0.05 and for ACQ r = − 0.45 p = 0.03) but not with baseline FEV1. Additionally, after BT improvements in asthma questionnaires were correlated with improvements in pre-bronchodilator FEV1 (% predicted) (r = 0.45 p = 0.03 for AQLQ and r = − 0.37 p = 0.08 for ACQ) . Baseline measurements of airway resistance were not correlated with baseline ACQ. No correlations were found between changes in AQLQ and ACQ questionnaires and airway resistance measured with bodyplethysmography.Regarding bodyplethysmography, a correlation was found between baseline AQLQ and baseline airway resistance (Raw) (r = 0.67 p = 0.0005 for pre-bronchodilator Rrs and r = 0.57 p = 0.005 for post-bronchodilator Rrs) and a trend between baseline AQLQ and pre-bronchodilator respiratory resistance at 5 Hz . Baseline ACQ scores were not correlated to baseline FOT measurements.Similar correlations were found for respiratory resistance measured with FOT at both 5hz and 19 Hz. Baseline AQLQ scores showed a significant positive correlation with respiratory resistance at 19 Hz  . A positive trend was found between ACQ improvement and baseline pre-bronchodilator respiratory resistance at both 5 Hz (r = 0.30 p = 0.16) and 19 Hz (r = 0.41 p = 0.05)  and improvement of AQLQ was correlated with a higher reactance at baseline . No significant correlation between baseline / change ACQ and airway reactance was found.Correlations between asthma questionnaires and reactance measurements were only found for AQLQ and reactance at 5 Hz: baseline AQLQ was negatively correlated with airway reactance  changes and FEV1 change. Although the differences were small, these data suggest that spirometry might improve after BT as previously shown in the RISA trial [1 was only visible in the patients that responded well to BT. This correlation was also explored, but not found in an Australian cohort of severe asthma patients [1 (% predicted) of 55% compared to 88%).Comparable to previously published larger trials , 21, spiSA trial . In our patients . An explWhen taking all patient data into account a significant increase was found after BT in post-bronchodilator bodyplethysmography airway resistance. This increase is mainly caused by one patient, who gained 7 kg during follow-up, which could explain this outcome. Similar to Langton et al.  no signiAn important finding of this study is the correlation between improvements on AQLQ and ACQ and respiratory resistance measured with FOT. In this study, patients with a higher respiratory resistance at baseline showed less improvements on both questionnaires after BT compared to patients with a lower resistance. Conventional spirometry and bodyplethysmography-determined airway resistance did not show this correlation. A possible explanation for this difference might be that FOT measures the respiratory resistance of the entire respiratory system, including smaller airways and surrounding tissue. Non-responding patients might be the patients with a higher resistance in surrounding tissue, potentially in the smaller distal airways which are not reached by the BT catheter. Consequently, patients with lower respiratory resistance at baseline might be the patients to select for BT treatment.An improvement in the respiratory resistance was not observed. Other recently published studies however did show an improvement of ventilation homogeneity after BT  and effeThere are limitations to this study that need to be addressed. The results in this study are part of the TASMA study, a multicenter study, however FOT measurements were only performed in one center. Therefore the present study included patients from one center only. Although single center results, the included group was clinically heterogeneous with allergic, eosinophilic and non-allergic/non-eosinophilic patients included. Additionally, patients were referred to this center from all parts of the Netherlands, thereby decreasing the effect of environmental factors on the outcome. Another limitation is the relatively small number of included patients. Although results need to be confirmed in larger trials, this study does offer important insights that may help to improve patient selection in the future. Strong points of this study are using not only conventional methods to assess lung function parameters but also use FOT, a method known to give a more reliable result on peripheral airway resistance. Also by keeping the medication use stable during follow up, and not start tapering down, which could influence the results, strengthens the observed measurements.1 improvement and asthma questionnaires improvement including AQLQ. Additionally, a lower respiratory resistance at baseline, measured with FOT, was associated with a favorable BT-response, which might reflect the main targeting of BT on the larger airways. These results add to understanding the mechanism of action of BT and might contribute to improved patient selection for this treatment.Pulmonary function parameters, including FOT, remained stable after BT. Correlations were found between FEV


To evaluate the effects of ventilator hyperinflation on respiratory mechanics.2O until a maximum pressure of 35cmH2O was reached, maintaining positive end expiratory pressure. After 35cmH2O was reached, the inspiratory time and respiratory rate were adjusted so that the inspiratory and expiratory flows reached baseline levels. Measurements of static compliance, total resistance and airway resistance, and peak expiratory flow were evaluated before the technique, immediately after the technique and after aspiration. Two-way analysis of variance for repeated measures was used with Tukey's post hoc test, and p < 0.05 was considered significant.A randomized crossover clinical trial was conducted with 38 mechanically ventilated patients with pulmonary infection. The order of the hyperinflation and control (without changes in the parameters) conditions was randomized. Hyperinflation was performed for 5 minutes in pressure-controlled ventilation mode, with progressive increases of 5cmHversus 52.0 ± 14.9 versus 52.3 ± 16.0mL/cmH2O; p < 0.001). There was a transient increase in airway resistance  and a transient reduction in peak expiratory flow  immediately after the technique; these values returned to pretechnique levels after tracheal aspiration. There were no changes in the control condition, nor were hemodynamic alterations observed.Ventilator hyperinflation increased static compliance, which remained at the same level after aspiration (46.2 ± 14.8 Ventilator hyperinflation promoted increased compliance associated with a transient increase in airway resistance and peak expiratory flow, with reduction after aspiration. Some factors, such as prolonged recumbency, neurodegenerative conditions, advanced age and smoking, may inhibit mucus mobilization and elimination and/or reduce the effectiveness of coughing.) In addition, some diseases, such as pneumonia, bronchiectasis, chronic obstructive pulmonary disease, cystic fibrosis and asthma have the potential to increase the production of airway secretions. Thus, the accumulation of secretions in the airways results from a combination of the underlying disease and abnormal mucociliary activity due to changes in mucus production and composition, ciliary structure and function, and the cough mechanism.Hospitalized patients exhibit excessive mucus production and impaired mucociliary clearance mechanisms.,5 These factors are related to an increased risk of secretion retention and the development of atelectasis due to airway obstruction, which may cause impaired gas exchange, pulmonary infection and fibrosis, and progressive reduction of lung compliance.,6During mechanical ventilation, the primary determinants for the increase in mucus viscosity and changes in mucociliary clearance are changes in the mucociliary system, artificial airway, complications related to immobility, acquired muscle weakness with an impact on cough efficacy, and inadequate humidification. and consists of increasing the inspired volume through adjustments of the mode and/or parameters of the mechanical ventilator. It aims to mobilize and remove pulmonary secretions from the peripheral airways to mitigate the complications associated with their retention.,9 Although there is no evidence of differences between MHI and VHI in terms of secretion clearance, respiratory mechanics or oxygenation, VHI has advantages related to the prevention of ventilator disconnection and the control of ventilatory variables. However, the effects of the VHI application method are worth mentioning. Studies have shown wide variability among ventilatory modes, and some results are unclear in terms of the precise adjustment of ventilatory parameters. Ventilatory adjustments have the potential to influence the movement of secretions and the gas distribution in the distal airways, which may affect the therapeutic effects.,12Lung hyperinflation can be performed manually (MHI), using a manual resuscitator or anesthesia bag, or by mechanical ventilation . VHI was initially described by Berney and DenehyThis is the first study to perform VHI in pressure-controlled ventilation (PCV) mode with individual adjustment of the inspiratory time according to the respiratory mechanics through a flow-time curve. The hypothesis of this study was that the adjustment of inspiratory time can optimize ventilation and increase the inspired volume, producing additional therapeutic effects on the displacement of secretions and on respiratory mechanics.The objective of this study was to evaluate the effects of VHI on the mechanics of the respiratory system in mechanically ventilated patients.Hospital Geral de Guarus located in Campos dos Goytacazes, state of Rio de Janeiro (RJ), Brazil. The study was approved by the Research Ethics Committee of the Institutos Superiores de Ensino do CENSA (ISECENSA), and the legal guardians of the patients signed an informed consent form.A randomized crossover clinical trial with 38 mechanically ventilated adult patients was performed at the st,rs) between 25 and 70mL/cmH2O and positive end expiratory pressure (PEEP) between 5 and 8cmH2O were included in the study. Patients with hemodynamic instability confirmed by a mean arterial pressure lower than 70 mmHg or high doses of vasoactive amines, undrained pleural effusion or pneumothorax, intracranial hypertension, bronchospasm confirmed by pulmonary auscultation, adult respiratory distress syndrome (ARDS) or decompensated congestive heart failure were excluded from the study.Patients older than 18 years who had pulmonary infection, had been mechanically ventilated for more than 96 hours under pressure-support ventilation (PSV) or PCV modes and had static compliance  conditions was determined by computer permutation, and the generated results were placed in envelopes numbered from 1 to 20, totaling 40 envelopes. The envelopes were opened sequentially at the time of data collection. The randomization process was hidden from the researcher. In addition, the bacteriological filter of the ventilator was replaced, the cuff pressure was increased and the circuits of the mechanical ventilator were checked for leakages.For both interventions, the patients were placed in the dorsal decubitus position with the headboard raised 45º; they then underwent closed tracheal aspiration according to the recommendations of the American Association for Respiratory Care (AARC).2O until a maximum pressure of 35cmH2O was reached according to patient tolerance, which was determined by the absence of coughing. PEEP remained unchanged throughout the study. After a maximum pressure of 35cmH2O (PCV + PEEP level) was reached, the inspiratory time was gradually increased until the inspiratory flow reached the baseline. Concurrently, the respiratory rate was decreased to allow the expiratory flow to also reach the baseline to avoid auto-PEEP. The technique was performed for 5 minutes and was followed by tracheal aspiration. For the CTRL condition, the patients were only positioned and aspirated, without changes in ventilatory parameters.The VHI technique with the adjustment of inspiratory time was performed in the PCV mode. The inspiratory pressure was gradually increased every 5 cmHimm) and 10 minutes after aspiration (POSTasp) using a Candle ventilator . The occlusion method was used at the end of inspiration in volume-controlled ventilation (VCV) mode, with a constant flow of 40L/minute and an inspiratory pause of 3 seconds. All patients were sedated (Ramsay 6). The ventilator screen was "frozen" to obtain the maximum pressures, P1 (the point separating the rapid and slow pressure drop immediately after the pause), plateau and PEEP, enabling the calculation of Cst,rs, total resistance (Rrs), airway resistance (Raw) and peak expiratory flow (PEF). Three consecutive measurements that were acceptable were taken at each time point, and the average of the two measurements with the lowest standard deviation was used. Each measurement was considered acceptable if no deflections were detected in the flow and pressure curves and/or there was no plateau along the inspiratory pause, which would suggest patient interference and the presence of leaks, respectively.Respiratory mechanics were evaluated before (PRE), immediately after the VHI or CTRL treatment  and peripheral oxygen saturation were monitored throughout the protocol using a DIXTAL 2030 multiparameter monitor . The study design can be observed in ® 12.01 software  was used to analyze the results.Mechanical measurements performed before and immediately after intervention and after aspiration were analyzed by two-way analysis of variance (ANOVA) for repeated measures with Tukey's post hoc test for results with normal distribution or with homogeneity of variances and were confirmed by the Shapiro-Wilk test and Levene's median, repectively. If the distribution was not normal, the Friedman test was used. A significance level of 5% was used. SigmaPlotA total of 38 patients were analyzed from August 2017 to March 2018. On the day of the study, all patients were under orotracheal intubation (OTI) or tracheostomy intubation and coupled to mechanical ventilation in the VCV or PCV mode. st,rs immediately after VHI compared with the pre-VHI value (p < 0.001) and remained constant after tracheal aspiration (p = 0.950). In the comparison between VHI and CTRL, Cst,rs was higher at POSTimm  and POSTasp , and there were no differences in PRE . The values are shown in The time-adjusted VHI increased Crs, Raw and PEF increased after VHI. Rrs increased immediately after VHI, without a statistically significant reduction after tracheal aspiration (p = 0.165). Comparing VHI and CTRL, Rrs was higher in the VHI in the POSTimm period  and POSTasp period , with no difference in the PRE . Raw increased immediately after VHI (p < 0.001), returning to baseline values after aspiration . Comparing VHI and CTRL, there was only a difference in the POSTimm period (p = 0.005); there were no differences in the PRE (p = 0.735) or POSTasp (p = 0.837). PEF decreased immediately after VHI (p = 0.034), returning to baseline values after aspiration . Comparing VHI and CTRL, there was only a significant difference in the POSTimm (p = 0.041); there were no differences in PRE (p = 0.243) or POSTasp (p = 0.350). No modifications were observed in Rrs, Raw or PEF in the CTRL condition.The variables Rversus 878.2 ± 219.2 versus 993.2 ± 345.2mL). The volumes increased by 117.7 ± 32.9% in PCV mode and by 144.6 ± 65.6% after the inspiratory time was adjusted. The inspiratory time obtained with VHI was 1.41 ± 0.35 seconds. No changes in heart rate, blood pressure or peripheral oxygen saturation were observed throughout the protocol in either group.During VHI, the inspired volume increased when the PCV mode was adjusted and after the time was adjusted  of 40cmH2O was reached. The authors observed that both techniques were equally effective for increasing Cst,rs and for the production of secretions, which increased by 11.6% after 30 minutes of VHI therapy and by 9.7% with MHI. In the present study, Cst,rs increased by 14.8% after 10 minutes of VHI with the optimization of inspiratory time. In another study comparing MHI and VHI, Dennis et al. performed a clinical trial with 46 patients with atelectasis or consolidation confirmed by X-ray. VHI was performed in synchronized intermittent mandatory ventilation (SIMV) with the VCV mode in four series of eight cycles. The volume was increased in 150-mL steps until a Pmax of 40cmH2O was reached or 250% of the tidal volume (TV) was obtained. However, the volume obtained during the interventions was not disclosed. The authors observed that VHI increased Cdyn,rs by 7.9%, but without differences between the techniques. In the present study, the inspiratory volume obtained was 244.6 ± 65.6% of the TV. Ahmed et al. compared the effects of MHI and VHI on 30 patients in the immediate postoperative period after mitral valve replacement. VHI was performed in the VCV mode with an increase in TV of 150%, a respiratory rate of 8 bpm, and a limited pressure of 35 mnHg (mean of 47.6cmH2O). Cdyn,rs increased by 6.6% after 1 minute of VHI; however, Cst,rs remained unchanged after 1 minute (5.6%) and after 20 minutes (4.8%). MHI did not modify Cst,rs and Cdyn,rs. Savian et al. conducted a randomized crossover clinical trial with 14 patients in a general intensive care unit (ICU) comparing MHI and VHI associated with different PEEP levels . VHI was performed in the VCV mode for 3 minutes with TV at 130%, limited pressure of 40cmH2O and respiratory rate adjusted between 7 and 8 pm, followed by tracheal aspiration. Both techniques also increased Cst,rs, but the results were only significant 30 minutes after VHI; an increase of 12% (6.0 mL/cmH2O) was observed, with no differences between PEEP levels. In the present study, there was an increase of 6.0 ± 9.9mL/cmH2O. Anderson et al. performed a systematic review comparing the effects of MHI and VHI on critically ill patients. Only these four previously cited clinical trials were selected for the analysis of the results. Assmann et al. performed a randomized crossover trial of 50 patients who received aspiration alone or VHI in VCV mode at 150% of the ideal tidal volume or in PCV mode with increments of 10cmH2O, and the maximum pressure was limited to 40cmH2O. VHI increased dynamic compliance and expired tidal volume, in addition to mobilizing a greater volume of secretions.Several authors have used C and 200mL or by means of fixed proportional increases of 130% or 150%,23 of TV. Lemes et al. performed VHI in PSV mode with a total pressure increase up to 40cmH2O; PEEP was maintained, and the patients were positioned in lateral decubitus. The authors observed a 13.8% increase in Cst,rs. Another study associated MHI with Flutter®-valve coupling to the expiratory port of the mechanical ventilator in a randomized crossover clinical trial. The authors used the PCV mode, with inspiratory pressure adjustment at 25cmH2O associated with Flutter-produced PEEP (approximately 14.7cmH2O) and a total maximum pressure of 40cmH2O. Silva et al. performed manually assisted cough with inspiratory pressure adjustment at 20cmH2O above the PEEP of 15cmH2O, for a total pressure of 35 cmH2O.Few studies have performed VHI in pressure-controlled modes (PCV or PSV). Most clinical studies performed VHI under controlled volume ventilation, with progressive volume increases between 150 analyzed the profiles of 64 Australian tertiary ICUs and found that 39% of the interviewees used VHI. Most respondents limited therapy by peak pressure and achieved an average of 37cmH2O, ranging from 25 to 40cmH2O. Physiotherapists using the VCV mode increased the inspiratory volume between 15 and 200%. In the ICUs that performed VHI using pressure-controlled modes, the pressure was increased stepwise from 2 to 5cmH2O. The application time ranged from 5 to 30 minutes. In the present study, increments of 5cmH2O were applied until a maximum pressure of 35cmH2O was reached for 5 minutes.Dennis et al. In addition, flow values close to the end of inspiration are associated with the terminal or peripheral airways. In some patients, increased inspiratory time promoted the cough reflex. When the pressure increased, the inspiratory volume increased 117.7 ± 32.9%, but the added inspiratory time increased the TV by 144.6 ± 65.6%. Silva et al., when performing manually assisted cough with VHI, increased the inspiratory time to 2 seconds for all patients, regardless of the respiratory mechanics. Berney and Denehy applied slow inspiratory flow (20Lpm) and 200mL increments in the TV until the maximum pressure reached 40cmH2O, with a consequent increase in inspiratory time. In the present study, the inspiratory time was individually adjusted according to the inspiratory and expiratory flow curves so that both reached the baseline. Thus, low flow values occurred at the end of inspiration.The effectiveness of bronchial hygiene is also related to inspiratory volume, elastic recoil pressure, pattern of secretion distribution and higher time constants. The increase in inspiratory time was associated with VHI, with the objective of increasing the inspiratory volume and distribution of ventilation in the alveolar units with high time constants. Patients with obstructive patterns seem to benefit from the increase in inspiratory time because they have "slow" flow patterns. For VHI or MHI to mobilize secretions, the inspiratory and/or expiratory flow rates must be modulated to favor the movement of secretions to the proximal airways. Thomas suggested three flow characteristics that may contribute to bronchial hygiene: (1) peak inspiratory flow (PIF) less than 90% of PEF; (2) PEF > 40L/minute; and (3) difference between PEF and PIF (bias flow) of at least 17 L/minute. The author analyzed the PCV mode using different combinations of inspiratory pressure adjustments , PEEP  and inspiratory time . The increase in inspiratory time was the variable that promoted the largest number of ventilatory combinations that met criteria 1 and 3.During mechanical ventilation, the ventilatory mode, the parameters used and the mechanical properties of the respiratory system may influence the mobilization of secretions and may result in the accumulation of secretions in the peripheral airways.2) are used to measure the hemodynamic impact of respiratory physiotherapy in the ICU.,18 During the techniques performed in the present study, no significant changes in blood pressure, heart rate or peripheral oxygen saturation were observed.Studies have shown that the MHI and VHI techniques promote the improvement of ventilatory parameters and respiratory mechanics without promoting hemodynamic changes. Measurements such as mean arterial pressure, heart rate and peripheral oxygen saturation (SpOThe main limitations of the present study were the absence of secretion volume measurement and blinding. Further studies are needed to evaluate the effects of technique optimization by increasing the inspiratory time and to determine the effects under specific disease conditions. Moreover, the measurement of the variables only 10 minutes after tracheal aspiration did not allow a determination of the duration of changes in the respiratory mechanics.Hyperinflation with mechanical ventilator promoted increased compliance associated with a transient increase in airway resistance and peak expiratory flow that decreased after aspiration.


Saliva can be used as an alternative diagnostic fluid enabling easy and non-invasive disease monitoring. Urea and creatinine can be measured in saliva and both were shown to be increased in renal failure. However, the dynamics of these markers during the development of kidney diseases is unknown. We aimed to describe the dynamics of salivary urea and creatinine in various animal models of acute kidney injury (AKI) and chronic kidney disease (CKD) and in patients with different stages AKI or CKD. Ninety Wistar rats underwent bilateral nephrectomy (BNX), ischemia–reperfusion injury (IRI) or glycerol-induced kidney injury to model AKI. CKD was modelled using 5/6 nephrectomy. In the clinical part 57 children aged 12.6 ± 4.9 years with AKI (n = 11) or CKD (n = 46) and 29 healthy controls (aged 10.2 ± 3.7 years) were enrolled. Saliva and blood samples were collected in both, animal experiments and the human study. In animal models of AKI, plasma urea and creatinine were higher than in controls. An increase of salivary urea and creatinine (twofold) was observed in BNX and IRI, but only after 12 h and 24 h, respectively. In glycerol nephropathy and 5/6 nephrectomy, salivary urea increased (by 100% and by 50%), while salivary creatinine did not change during the observation period. Salivary urea and creatinine were significantly higher in all patients compared to controls (threefold) and in both, AKI and CKD they were associated with the severity of renal failure. Plasma and salivary concentrations correlated only in children with renal failure , but not in controls . Our study indicates that during the development of renal impairment saliva could be used for non-invasive monitoring in higher stages of AKI or CKD, rather than for screening of early stages of kidney diseases. Repeated blood sampling needed for monitoring of renal functions is associated with a risk of complications4. In combination with haemodialysis, repeated blood collections increase the risk for infections5. Using saliva as the diagnostic fluid represents a non-invasive alternative, collection can be conducted at home and does not require trained personnel6. These advantages are of special importance for children and elderly patients with comorbidities.Widely used markers for the assessment of kidney functions are creatinine and urea measured in blood plasma10. On the other hand, other studies have shown that concentrations of salivary urea and creatinine in patients with early stages of kidney disease (stage 2 and 3) were similar to those in healthy controls. Significantly higher concentrations of salivary urea and creatinine were found only in patients with more severe kidney disease (stage 4 and 5)11. In some studies, a positive correlation between plasma and salivary concentrations of urea and creatinine has been revealed only in patients with kidney disease, not in healthy controls13. On the contrary, others have shown a relation between plasma creatinine and urea and their salivary concentrations in both, healthy controls and patients with kidney disease15. These contradictory results prevent the use of saliva for the assessment of kidney function in the clinics. One of the reasons for the differences between studies may be the different disease severity of the studied patient population. It has been shown that adult and pediatric patients with a higher stage of CKD have also higher salivary markers of renal function11. In addition, a decrease in salivary urea and creatinine was observed in patients after kidney transplantation and after dialysis13.Several clinical and experimental studies have demonstrated increased levels of salivary urea and creatinine in individuals with AKI as well as with CKD in comparison to healthy controls. Moreover, the lowest concentrations were found in patients with early stages of kidney disease which increased with the severity of kidney disease18. The largest study published so far focusing on salivary creatinine has shown that serum creatinine can be deduced from its salivary concentrations18. However, this was true only for patients with higher stages of CKD. None of the studies analysed the dynamics of salivary markers of renal function during the development of renal diseases. It is also not clear whether saliva can be used for the screening of early stages of kidney diseases.Previously published studies—either clinical or experimental—focused on single time pointsOur study aimed to evaluate salivary urea and creatinine dynamics in the development and progression of kidney failure using multiple models of AKI and CKD and to confirm these findings in a pediatric cohort of patients with different stages of AKI or CKD.Animal experiments were conducted according to the guidelines for laboratory studies performed on animals approved by the Ethics Committee of the Institute of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia. Young adult male Wistar rats were used . Animals were in controlled light/dark cycle room, with ad libitum food and water access, with constant temperature (22 ± 2 °C) and humidity (45–65%).19. Animals (n = 11) were anesthetized with ketamine and xylazine . Ophthalmic lubricating ointment was applied to the eyes. The skin was disinfected using betadine. Retroperitoneal incision was made on one side and the renal pedicle was identified. The kidney was decapsulated and renal pedicle was ligated with a suture. The kidney was removed on both sides. The muscle layer was closed using an absorbable suture . The skin was closed using clips . Control animals (n = 9) underwent the same procedure but the pedicle was not tied off and kidneys were only decapsulated.After 2 weeks of acclimation period, rats were divided into eight groups. To model AKI, 3 different animal models were used: bilateral nephrectomy—BNX, ischemia reperfusion injury – IRI and glycerol-induced nephropathy. Bilateral nephrectomy was performed in one surgical session as described previously20. Ventral approach was used and both kidneys were exposed. In ischemic phase, micro clamps were applied on renal pedicles for 30 min. Kidneys with attached clamps were returned to the abdominal cavity. After 30 min, clamps were released. The muscular layer was closed with an absorbable suture. The skin was closed using clips. The reperfusion phase lasted 48 h. The sham animals (n = 9) underwent the same procedure but pedicles were only gently decapsulated, not clipped.To induce IRI (n = 11), rats were anesthetized as mentioned above and surgery was performed as described previously21. Briefly, rats in AKI group received single-dose of glycerol equally into both hind limbs. The control group (n = 9) received saline in the same manner.To induce glycerol-induced nephropathy (n = 11), glycerol  was applied intramuscularly as described previously g for 10 min. Plasma was stored at − 20 °C until analysis. Prior to saliva collection, rats were anesthetized using ketamine and xylazin as mentioned above. Salivation was induced by intraperitoneal injection of pilocarpine  at same time points as blood collection. Saliva samples were collected using pipettes from the oral cavity into sterile tubes for 30 min.In all models, blood was collected from the tail vein into microvettes  at baseline and 3, 12, 24 and 48 h after induction of AKI. Blood was centrifuged at 1600 22. Animals were anesthetized, a retroperitoneal incision was made on the left side and the kidney was exposed. Two thirds of the left kidney were removed. Bleeding was stopped using absorbable gelaspon . The muscular layer was closed using an absorbable suture. The skin was closed using metal clips. After 2 weeks of recovery, a retroperitoneal incision was made on the right side. The renal pedicle was ligated with a suture, the kidney was decapsulated and removed. In the sham group (n = 13), the kidneys were only decapsulated. Blood was collected from the retroorbital plexus at baseline and after 2, 4 and 6 months after the second surgery. Plasma was stored at – 20 °C until further analysis. Salivation was induced using pilocarpine as described above at the same time points.To induce CKD, 5/6 nephrectomy (n = 17) was performed in a 2-step surgery24. Estimated glomerular filtration rate was calculated according to Schwartz’s equation25. Clinical characteristics of the patients are shown in supplementary Table 3EDTA tubes  after overnight fasting in both, healthy controls and patients. Whole unstimulated saliva was collected for 15 min by passive drooling and spitting into sterile collection tubes to a final volume of at least 1 ml . To prevent saliva contamination, all participants were asked not to eat, drink or brush the teeth at least 60 min before collection. Health questionnaire assessing general and oral health was filled by the legal guardians. Blood and saliva samples were centrifuged at 1600 g for 10 min. The supernatants were stored at − 20 °C until further analysis. Legal guardians of all children have signed written informed consent. This part of the study was conducted according to the principles expressed in the Declaration of Helsinki and according to approvals of the Ethics Committee of the National Institute of Children’s Diseases at the Faculty of Medicine, Comenius University, Bratislava, Slovakia.A cross sectional study with age-matched control group was performed. Eighty-one consecutive children with AKI or CKD were enrolled in this study aged 12.6 ± 4.9). All patients attended the Pediatric nephrology clinic at the National Institute of Children’s diseases, Faculty of Medicine, Comenius University in Bratislava, Slovakia. Patients were enrolled between April 2017 and December 2019. All patients were diagnosed according to Kidney Disease Improving Global Outcomes (KDIGO) guidelines2.6 ± 4.9Urea was measured using a commercial kit and spectrophotometric quantification in plasma and saliva . For plasma analyses, samples were diluted 1:9, for saliva, samples were diluted 1:1 with distilled water. Absorbance was measured after 30 min of incubation with reagents at room temperature at 450 nm. Limit of detection (LOD) and limit of quantification (LOQ) were 0.05 mmol/l and 0.14 mmol/l respectively. Sensitivity and specificity were calculated as 86.8% and 59.3%, respectively with a cut-off value of 0.15 mmol/l. Area under the receiver operating characteristic (ROC) curve was 0.80  and a spectrophotometric quantification. Briefly, 15 µl of plasma or saliva were transferred into a 384 well plate and absorbance was measured after 1 min and after 30 min of incubation with reagents at 490 nm. LOD and LOQ were calculated as 6.4 µmol/l and 21.1 µmol/l, respectively. Sensitivity and specificity were 87% and 65.5% with cut off value 15.3 µmol/l. Area under ROC curve was 0.80  was used for power analysis and determination of required sample size. Given alpha = 0.05, power = 0.80, d = 0.82 for salivary urea and d = 0.72 for salivary creatinine, the total sample size calculated was 50 for salivary urea and 62 for salivary creatinine respectively. GraphPad Prism 6.01  was used for statistical analysis. All data were tested for normality using D’Agostino Pearson omnibus normality test. To get normal distribution of data that were not normally distributed, plasma concentrations of creatinine and salivary concentrations of urea and creatinine were log-transformed. To compare concentrations of urea and creatinine between healthy participants and patients with kidney disease, Student’s t-test was used. To compare concentrations of urea and creatinine in different stages of AKI, the Kruskal–Wallis test and subsequently Dunn’s multiple comparison test were used. To compare concentrations of urea and creatinine within stages of CKD, one-way ANOVA and subsequently Dunnett’s multiple comparison test were used. To compare concentrations of urea and creatinine in animal models, two-way ANOVA was used  with subsequent Sidak's post-hoc multiple comparison tests. Pearson’s correlation analysis was used to evaluate differences between plasma and salivary concentrations in both, animal models and clinical samples. All values are expressed as mean + /− SD. P values below 0.05 were considered as statistically significant.Animal experiments were approved by the Ethics Committee of the Institute of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava, Slovakia. Clinical part of the study was conducted according to the principles expressed in the Declaration of Helsinki and according to approvals of the Ethics Committee of the National Institute of Children’s Diseases at the Faculty of Medicine, Comenius University, Bratislava.Informed consent was obtained from legal guardians of all participants.In bilateral nephrectomy (BNX), plasma urea and creatinine were 40% higher than in sham controls after 3 h , plasma urea was significantly higher in comparison to sham controls 3 h after induction of IRI . There seemed to be a threshold concentration to be reached in plasma for both markers; 11 mmol/l for BUN  and 160 µmol/l for creatinine  as determined by our experiments.Both, plasma urea and creatinine concentrations were significantly higher in children with kidney diseases regardless of stage in comparison to healthy controls . Nevertheless, both the study and the experiment showed the salivary creatinine and BUN to be useful markers of kidney damage once the plasma thresholds are reached. It is worthy to note, that in 5/6 nephrectomy animals did not reach the plasma threshold of 160 µmol/l for creatinine or 11 mmol/l for BUN after six months. On the other hand, this was the opposite in children. Moreover, children are also likely those who would benefit the most from this approach, once salivary-based diagnostics is established in nephrology due to stress-free sample collection36. Novel biomarkers of kidney function or injury are being investigated, but an optimized protocol for the collection and processing of saliva samples as well as analysis of salivary concentrations is lacking. A multi-omics approach without a priori hypotheses would likely be more appropriate37 and will be used in a follow-up study. Last but not least, glomerular filtration is not the only function of the kidney. Creatinine or urea cannot be used for the assessment of any of the other endocrine or metabolic functions.A conceptual shortcoming is the focus on urea and creatinine, which are far from being ideal biomarkers even if measured in blood plasmaThis study is the first to observe the dynamics of urea and creatinine in plasma as well as in saliva in animal models of AKI and CKD. Salivary markers of renal function increase during the development of renal failure, but later than in plasma. This is in line with the clinical data showing higher salivary urea and creatinine only in patients with the highest stages of AKI or CKD. In summary, we have shown that salivary urea and creatinine are potential biomarkers of renal function, usable for non-invasive monitoring of higher stages of AKI and CKD, but not for screening of early stages of renal diseases.Supplementary Information.


Background Tourniquets are commonly used to reduce bleeding intraoperatively during orthopedic surgery. There are variable guidelines for ideal tourniquet pressure and duration; the practice of fixed, high tourniquet pressures remains common. The purpose of this study was to assess the correlation between excessive tourniquet pressure and duration and the incidence of tourniquet pain in foot and ankle surgery patients.Methods A retrospective cohort study was conducted on 128 patients who underwent foot and ankle surgery with tourniquet use. Baseline systolic blood pressure (SBP), tourniquet pressure and duration, intraoperative opioid consumption, post-anesthesia care unit (PACU) pain scores, PACU opioid consumption, and PACU length of stay (LOS) were collected. Linear regression analysis was used to test for the statistical correlation between the tourniquet pressure and duration and postoperative pain scores, narcotic use, and PACU LOS.ResultsN = 128). Only 2.5% of the patients had tourniquet pressures 100-150 mmHg above SBP. The mean tourniquet time was 107.5 minutes ± 39.8. Linear regression showed a significant positive correlation between tourniquet time and morphine equivalents used in the perioperative period  and the length of PACU stay .A tourniquet pressure of 280 mmHg was used in 90% of the cases (Conclusion Prolonged tourniquet times at high pressures, not based on limb occlusion pressure LOP, lead to increased pain and opioid use and prolonged PACU LOS. Basing tourniquet pressures on LOPs could likely improve the safety margin of the tourniquets; however, randomized clinical trials are needed. The tourniquet is commonly used in orthopedic surgeries on the upper and lower extremities to reduce blood loss, improve visualization, and expedite the surgical procedure. However, tourniquets have been associated with multiple local and systemic complications causing significant morbidity to patients. Tourniquets can cause pain, paralysis, damage to local skin, vasculature or neuromuscular structures, thrombosis and pulmonary embolism, compartment syndrome, reperfusion syndrome, and tourniquet pain syndrome . Rarely,Patients who receive sufficient surgical block with regional anesthesia can still experience tourniquet pain postoperatively . The etiUnfortunately, there is a lack of consensus in the surgical community regarding safe and effective tourniquet pressure and duration of use, and practice remains highly variable. The Association of Surgical technologists recommends tourniquet pressures of 100 mmHg above systolic blood pressure (SBP) for the lower extremity, while Kam et al. suggest that a range of 100-150 mmHg above the SBP is acceptable and Wakai et al. expands this range to 90-150 mmHg above SBP for the lower extremity or 50-75 mmHg above the limb occlusion pressure (LOP) ,6,10. NoThis retrospective study aims to add to the literature by assessing for the correlation between excessive tourniquet pressure and duration and the increased incidence of tourniquet pain in foot and ankle patients. With increased awareness of the potential complications that tourniquets play in the role of postoperative pain, new parameters regarding tourniquet use intra-operatively can lead to decreased incidence of tourniquet side effects and potentially lead to a change in our practice regarding tourniquet use.This study was approved by the University of Alabama at Birmingham’s (UAB) Institutional Review Board. Patients who met the following criteria were included in this study: 18 years of age or older, underwent foot and ankle surgery, received a preoperative regional nerve block for postoperative analgesia, and received intraoperative use of a tourniquet. We excluded patients who had a history of daily opioid use of more than 30 mg oral morphine equivalents (OME) for more than 30 days, with the preexisting preoperative pain score greater than five out of 10 on the visual analog scale (VAS), underwent foot and ankle surgery without a regional nerve block, were deemed regional block failures by the regional anesthesia provider, did not have the peripheral nerve block type recorded, or underwent foot and ankle surgery without tourniquet use.Chart review and data extractionData were extracted by a single, independent author. The variables of interest for this study were patient’s baseline SBP, tourniquet pressure and duration, tourniquet deflation time, tourniquet reinflation pressure and duration, start time of BP and heart rate changes, intraoperative opioid consumption before BP and heart rate changes, intraoperative opioid consumption after BP and heart rate changes, BP and heart rate changes after deflation, post-anesthesia care unit (PACU) pain scores, PACU opioid consumption, and PACU length of stay (LOS). Opioid use was converted to OME for a standardized comparison.Statisticst-test . For data that are not normally distributed, the Kruskal-Wallis and Mann-Whitney tests were used for comparisons. Chi-square and Fisher’s exact tests were used to analyze categorical data. Pearson correlation test and linear regression statistics were used to test the relationship between pain scores and tourniquet use parameters, while controlling for relevant clinical and demographic variables. A p-value of <0.05 was considered statistically significant.Statistical analysis was performed using SPSS version 25 . Demographic and clinical variables with continuous measures were expressed as means and standard deviations; categorical variables were expressed as proportions. Continuous data were analyzed using the Kolmogorov-Smirnov test  and the one-way analysis of variance (ANOVA) and Student’s Between August 2015 and December 2015, 128 patients  met the study inclusion criteria. The patient characteristics of these 128 patients are shown in Table OutcomesThe mean opioid use before hemodynamic changes was 34 mg OME  and after hemodynamic changes 12.5 mg OME .p < 0.001).As seen in Table The mean tourniquet pressure for all patients was 280.1 mmHg ± 6.5 . Tourniquet pressure was 280 mmHg in 90% of patients in the "long" tourniquet group (74 of 82 patients). Among the 81 patients for whom both SBP and tourniquet pressure were available, the mean tourniquet pressure above SBP was 176.6 mmHg ± 15.3 . Only 2% of patients had tourniquet pressures within 90 to 149 mmHg above SBP . PACU discharge pain scores were available for 33 patients; the mean pain score at discharge was 2 ± 2.4 .N = 117; r = 0.410; p < 0.001) and PACU LOS  as shown in Figure N = 30; r = 0.026; p = 0.891).Pearson correlation test showed a significant positive correlation between the tourniquet time and the OMEs used in the perioperative period , PACU LOS , or PACU discharge pain scores .Tourniquet pressure was not significantly correlated with OMEs used in the perioperative period , PACU LOS , or PACU discharge pain scores . There was no significant correlation between the difference between the tourniquet pressure and the patient’s SBP and the morphine equivalents used in the perioperative period .Tourniquets are used in orthopedic surgeries to reduce bleeding, but postoperative pain is among the possible complications. Various guidelines exist regarding ideal tourniquet pressure and duration, but the practice of fixed, high tourniquet pressures remains common. The purpose of this study was to assess the correlation between excessive tourniquet pressure and duration and the increased incidence of tourniquet pain in foot and ankle surgery patients.N = 603) by Kruse et al. comparing postoperative opioid use in first 24 hours in patients undergoing total knee replacement with and without the use of intraoperative tourniquet showed an increased tourniquet time was associated with increased opioid use, with every additional 10 minutes of tourniquet time leading to an additional 0.43 mg of opioid consumption [Tourniquet time was found to positively correlate with greater opioid use in the perioperative period and longer duration of stay in the PACU. Long tourniquet times (≥90 minutes) were also associated with significantly greater intraoperative opioid use than short tourniquet times (<90 minutes). These findings are consistent with previous studies in the orthopedic literature. A retrospective review  leads to more postoperative complications and longer hospital stay . By contNo strict consensus exists on ideal tourniquet time. The existing literature recommends 1 to 3 hours as a safe limit for tourniquet time, and if the anticipated surgery time is >2.5 h, the tourniquet should be deflated for 10-15 minutes before re-inflating again . Other sThis study found poor compliance with the tourniquet use guidelines at our institution. Tourniquet pressure was 280 mmHg in 90% of patients, while only 2.5% of the patients had tourniquet pressures between 100 and 150 mmHg above SBP. These findings were in line with a survey by Delougry et al. who reported that the majority of orthopedic surgeons were not aware of the used tourniquet pressure and preferred to use fixed pressures for upper extremity (250 mmHg) and lower extremity (300 mmHg) procedures, without considering the patient’s baseline blood pressure .The clinical implications of widespread improper tourniquet use should not be underestimated. Increased perioperative opioid consumption has been shown to correlate with hyperalgesia and an increased opioid tolerance -21. TourN = 82) in whom both tourniquet pressure and SBP were recorded. Larger studies are needed to establish the presence or absence of relevant correlations between this pressure difference and opioid use, LOS, and complication rates. Although this study was unable to find a statistically significant correlation between the difference of tourniquet pressure and SBP and opioid use in the perioperative period, it seems plausible that such a relationship could exist. Thus, this lack of a finding may represent a type II error caused by the small number of patients (The primary limitations of this study were those inherent to all retrospective studies. In addition, this study was limited by a lack of spread of tourniquet pressures, which likely limited its ability to find the correlations between the tourniquet pressure and postoperative pain, opioid use, or PACU LOS. Opioid use may have confounded the associations observed between the tourniquet time and PACU LOS, due to the delay caused by the administration of opioids. Finally, the study was limited by missing outcomes data that may have reduced the statistical power and significant correlations.The majority of cases of foot and ankle surgery at our institution did not adhere to the current tourniquet use guidelines, which recommend a tourniquet pressure between 100 and 150 mmHg above the patient's SBP. Prolonged tourniquet times at high pressures not based on LOP, as observed in our study, lead to increased pain and opioid use postoperatively and prolonged time in the PACU. Basing tourniquet pressures on LOPs could likely improve the safety margin of tourniquet use in foot and ankle surgery; however, future investigations in the form of prospective randomized studies are warranted.


Background: The population with myocardial infarction (MI) undergoing primary percutaneous coronary intervention (PPCI) is growing, but validated models to guide their clinical management are lacking. This study aimed to develop and validate prognostic models to predict major adverse cardiovascular events (MACEs) in patients with MI undergoing PPCI.Methods and Results: Models were developed in 4,151 patients with MI who underwent PPCI in Fuwai Hospital between January 2010 and June 2017, with a median follow-up of 698 days during which 544 MACEs occurred. The predictors included in the models were age, a history of diabetes mellitus, atrial fibrillation, chronic kidney disease, coronary artery bypass grafting, the Killip classification, ejection fraction at admission, the high-sensitivity C-reactive protein (hs-CRP) level, the estimated glomerular filtration rate, the d-dimer level, multivessel lesions, and the culprit vessel. The models had good calibration and discrimination in the derivation and internal validation with C-indexes of 0.74 and 0.60, respectively, for predicting MACEs. The new prediction model and Thrombolysis in Myocardial Infarction (TIMI) risk score model were compared using the receiver operating characteristic curve. The areas under the curve of the new prediction model and TIMI risk score model were 0.806 and 0.782, respectively .Conclusion: The new prediction model could be used in clinical practice to support risk stratification as recommended in clinical guidelines. Improving the quality and management of acute coronary syndrome contributed substantially to patients with cardiovascular disease. Although many clinical guidelines have been established, only a few tools are available to assess the incidence of major adverse cardiovascular events (MACEs) among patients with myocardial infarction (MI) undergoing primary percutaneous coronary intervention (PPCI) and to guide patients' clinician communication and long-term risk management.Calculated risk scores were used to develop a model that can further evaluate 1-, 2-, 3-, and 5-years risks of MACEs among patients with MI who underwent PPCI.This risk score incorporates routine clinical data, biochemical tests, and coronary angiography findings, which are routinely evaluated in the clinical assessment of patients with MI who underwent PPCI. The risk score model can help doctors identify patients most at risk of MACEs.Cardiovascular disease (CVD) has become the leading cause of mortality worldwide  and a maTo achieve precision medicine, healthcare decisions, practices, and interventions should be individualized on the basis of each patient's predicted risk of disease. In this study, we sought to develop a risk score model to evaluate 1 -, 2 -, 3-, and 5-years risk for patients with MI who underwent PPCI. This article was prepared in accordance with the TRIPOD reporting checklist 1.A total of 4,151 consecutive patients with MI who underwent PPCI at Fuwai Hospital in Beijing, China, between January 2010 and June 2017 were enrolled. All patients were diagnosed with MI according to established guidelines . The derThe enrolled patients provided informed consent, and the study was approved by the Ethics Committee of Fuwai Hospital. The study flowchart is shown in Thrombolysis in Myocardial Infarction (TIMI) flow grade three levels less after PPCI was defined as a no-reflow phenomenon. For adverse events that occurred at follow-up, the following events were evaluated: all-cause mortality, cardiac mortality, MI recurrence, and stroke (ischemic stroke). The objective end-point index was evaluated using a single-blind method.The patients were followed up at least 1 year after discharge. The health status of the enrolled patients was confirmed through telephone calls and review of health records, and this method was approved by the Review Board of Fuwai Hospital. The physicians in charge of the follow-up identified and extracted primary endpoints from hospital records, laboratory reports, and clinical notes in the event of death.P < 0.2 for predicting MACE. The following variables were included to calculate major adverse CVD risk: sex, age, a history of hypertension, atrial fibrillation, a history of coronary artery bypass grafting (CABG), a history of PCI, diabetes status, blood pressure, the creatinine (Cr) level, the estimated glomerular filtration rate (eGFR), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), lipase activator (LPA), and coronary angiography findings.The normal distribution of the outcome variables was confirmed by the Kolmogorov–Smirnov test. For the randomization procedure, all enrolled patients were numbered 1 to 4,103. Then, cells were filled in with “=RAND ” to create a list of randomized numbers and then sorted. The first 3,078 patients were derived queues, and the second 1,025 patients were validated queues. Baseline parameters during follow-up are presented as median [standard error (SE)] for continuous variables and as frequency and percentage for categorical variables in the table presenting the characteristics of the derivation cohort and validation cohort . The varThe least absolute shrinkage and selection operator (LASSO) method was used to screen the independent variables to realize the reduction and simplification of the model and to prevent overfitting. Multivariable Cox regression was used to develop a novel prediction risk score for MACEs using all pre-specified variables . In thisAt the beginning of the model establishment, all identified independent variables were selected to minimize model deviation caused by non-inclusion of important independent variables. Furthermore, the established model needs to find the set of independent variables with the strongest explanatory power for the dependent variables to improve the prediction accuracy. As a result, we included the LPA, HDL-C, and TG, which failed to have statistical significance by Cox regression in the LASSO regression. Therefore, index selection is significant in the modeling process. The 1996 LASSO algorithm is a compressed estimate method that simplifies the index set. A more refined model is obtained by constructing a function that compresses some coefficients and sets some coefficients to 0, 0.5, or minimization. LASSO regression is a biased estimation of data with complex collinearity and retains the advantage of contraction. LASSO programming is provided by the Lars algorithm software package of R language. Therefore, dimensionality reduction and variable selection can be achieved accurately by LASSO regression.P-values were two-tailed, and statistical significance was determined at P < 0.05.The corresponding nomogram prediction model was drawn according to the regression coefficient of the selected independent variables. For the variables selected in the nomogram prediction model, values of the variables can correspond to the scores on the integral line at the top of the nomogram (the score ranged from 0 to 550 points) through the projection of the vertical line, and the total score can be obtained by adding the scores corresponding to the values of each variable. The cumulative occurrence probability of MACEs at 1, 2, 3, and 5 years can be obtained from the total score on the prediction line at the bottom of the nomogram. To reduce overfitting, the self-sampling method was used to verify the nomogram prediction model. Model discrimination was quantified using Harrell's c-statistic and calibration chart. Hypertension, hyperlipidemia, a history of PCI, smoking status, sex, blood pressure, body mass index, LDL-C, HDL-C, TG, left main (LM) artery lesion, and no-flow phenomenon were controlled to draw the receiver operating characteristic (ROC) curve. The LASSO method adopts the glmnet package of R language for variable selection and the RMS package of the R language for drawing and internal verification of the nomogram . Cox regression analysis was performed using the survival package. Stdca.r was used to draw the clinical decision curve. The main statistical analysis software used in this study was the R language version I 386 3.6.2. Other analyses were performed using SPSS Statistics version 20.0 . All R2, Harrell's c-statistic) were calculated. The calibration and discrimination performance of the equations developed in the derivation subcohort were assessed in the validation subcohort and compared with the performance of models developed in the entire cohort; baseline survival functions and hazard ratios (HRs) were also compared.The 1-, 2-, 3-, and 5-years baseline survival probabilities of each model were obtained using R language version I 386 3.6.2 commands that were utilized to fit the models. Calibration performance was assessed graphically at 1-, 2-, 3-, and 5-years MACE risks by plotting the predicted 1-, 2-, 3-, and 5-years risks against the observed 1-, 2-, 3-, and 5-years risks. The flawlessly calibrated curve was represented by a diagonal line with a slope of 1. The observed 1-, 2-, 3-, and 5-years risks were obtained using the Kaplan–Meier method, and the slopes of regression lines comparing the predicted with the observed 1-, 2,- 3-, and 5-years risks were calculated. Standard statistical metrics of model and discrimination performance  curve using a non-parametric test developed by DeLong et al. MedCalc for Windows version 18.2.1  was used for comparison.The study population included 4,151 men and women aged 24–97 years during risk assessment from January 1, 2010, to June 30, 2017 . Forty-eP = 0.053), hypertension (P = 0.013), diabetes mellitus (P < 0.0001), a history of atrial fibrillation (P < 0.0001), chronic kidney disease , a history of CABG (P < 0.0001), the Killip classification (P < 0.0001), ejection fraction (EF) grade (P < 0.0001), high-sensitivity C-reactive protein (hs-CRP) (P < 0.0001), eGFR (P < 0.0001), the d-dimer level (P < 0.0001), the Cr level (P < 0.0001), the use of intra-aortic balloon pump (P < 0.0001), a LM coronary artery lesion (P < 0.0001), the no-reflow phenomenon (P = 0.006), complete revascularization during hospitalization (P < 0.0001), triple-vessel lesions (P < 0.0001), culprit lesions including those in the left circumflex artery  and LM artery (P < 0.0001), the elevated LPA level (P = 0.343), the HDL-C level (P = 0.50), the TG level (P = 0.173), etc.The following variables are shown in d-dimer level, the culprit lesion, and mutivessel lesions) were included in the model.Twenty-eight variables were filtered by the LASSO regression method, as shown in P = 0.0175), atrial fibrillation , CABG , EF grade at admission ≤45 , and multivessel lesions  were relevant factors for MACEs during follow-up. The forest plot is shown in The multivariable Cox regression model established by the variables screened by LASSO method is shown in d-dimer, the number of culprit lesions, and multivessel lesions were all statistically significant predictors of MACE risk  through the projection of the vertical line, and the total score can be obtained by adding the scores corresponding to the values of each variable. The cumulative occurrence probability of MACEs at 1, 2, 3, and 5 years can be obtained from the total score on the prediction line at the bottom of the nomogram. The scores, ranging from 0 to 550 points, were assigned as follows: age < 40 years, 28.01; age 40–50 years, 18.68; age 50–60 years, 9.34; age ≥60 years, 0; diabetes mellitus, 30.1; without diabetes mellitus, 0; atrial fibrillation, 43.5; without atrial fibrillation, 0; history of CABG, 88.9; without history of CABG, 0; history of CKD, 59.7; without history of CKD, 0; Killip I, 0; Killip II, 33.3; Killip III, 66.7; Killip IV, 100; EF at admission ≤45%, 31.1; EF at admission between 45% and 55%, 15.6; EF at admission >55%, 0; hs-CRP concentration that varies from 3.5 to 10 mg/L and over 10 mg/L, 16.1 and 32.3, respectively; hs-CRP concentration ≤3.5 mg/L, 0; eGFR of 60–90 mL/min and <60 mL/min, 23.3 and 46.5, respectively; eGFR >90 mL/min, 0; z statistic, 1.718). Model discrimination was quantified using Harrell's c-statistic and calibration chart. The predicted vs. observed 1-, 2-, 3-, and 5-years risk plots for MACEs using the risk prediction model showed excellent calibration performance . Figure Patient management and assessment should be individualized and precise to ensure the sustainable development of the contemporary healthcare system. For patients with ACS, care should be appropriate for the disease type and stage; however, only a few tools can be used to assist medium- to long-term management of patients with MI undergoing PPCI . PatientWe have developed a risk score model to evaluate the 3- and 5-years risk probability for patients with MI who underwent PPCI, and this model can be used by specialists and primary healthcare professionals to enhance risk management and assessment. This risk score model incorporates routine clinical data on serum inflammatory factors and coronary angiography findings by integrating time since event, and it allows re-evaluation of the risk of MACEs 3 years or more following PPCI. The established risk score may be used to inform decisions about novel therapies and be tested in the context of changes in quantifiable risk.P = 0.043), the model was established by derivation only, and the models had good calibration and discrimination in derivation and internal validation by the C-index and calibration graph for predicting MACE. Therefore, the proposed model does not increase the risk of recurrent MI.The enrolled patients with acute MI who underwent PPCI are the most appropriate population to develop or validate a risk prediction model for MACE. However, similar cohorts are rare. While there was a statistically significant difference between the derivation and validation cohorts in terms of recurrent MI , which were assigned 28.01, 18.68, 9.34, and 0 points in the nomogram. These results were consistent with those of Dawson et al. ; that isd-dimer were significantly correlated with a greater risk for MACE. The early inflammatory response is generated by proinflammatory cytokines, with important biological functions in the cascading inflammatory reaction and critical role in the occurrence and development of acute ischemic injury. T lymphocytes, mast cells, and macrophages play critical roles in the pathogenesis of MI treated with PPCI. Furthermore, serum biomarkers reflecting systemic inflammatory levels may help establish proper clinical management and therapeutic schedules. In this study, the serum concentration of hs-CRP that varied from 3.5 to 10, and >10 was assigned 15.9 and 31.7 points, respectively. The scores of the high d-dimer concentration (≥0.5) and triple-vessel lesions were 27.2 and 34.2, respectively. Inflammation markers including hs-CRP and d-dimer contributed substantially to the prediction score model after screening by LASSO regression. Moreover, the role of inflammation level has been proved in plaque ruptures. Therefore, anti-inflammatory approaches could benefit patients by significantly reducing levels of serum inflammation biomarkers. Acute MI can be viewed on a life-course continuum, progressing from the presence of risk factors to occurrence of subclinical atherosclerosis and MI induced by plaque rupture. Numerous risk scores contribute to the management and primary prevention of MI . One of the most comprehensive equations was from the UK QRISK3  were risk factors of MACEs during a median follow-up of 698 days, which is consistent with previous studies.Incorporating acute phase inflammation factors into the prediction model of long-term events based on previous literature is reasonable. Robust evidence –24 has sus study  revealedus study . Hs-CRP 2 and <45 mL/min/1.73 m2 predicted MACEs . In the present study, we included CKD history and eGFR levels on admission into the prediction model. eGFR tested post-PPCI reflects the renal function at that time and is non-repeatable, given the variations in CKD history.CKD is correlated with a high risk of mortality from CVD , and patA substantial proportion of patients still had myocardial tissue hypoperfusion after PPCI, which is termed as no-reflow phenomenon caused by microvascular obstruction –33. PrevThis study developed a risk score model to evaluate 3- and 5-years risks of patients with MI who underwent PPCI. The researchers followed strict inclusion and exclusion criteria, which enabled a reasonably streamlined and comparable hospital flow for all patients. The model incorporated variables including routine clinical data, serum inflammatory factors, coronary angiography findings, and other relevant clinical parameters that are commonly included in clinical assessment. These variables are routinely documented in electronic health records; therefore, their collection is not linked with extra costs.d-dimer, hs-CRP, and EF are not routinely obtained as the standard of care for MI patients. Inclusion of these variables may increase the chance of having missing information and inability to calculate the risk score. Finally, patients have been enrolled over a long time period, which could have confounding effects due to improvements in interventional techniques and progress in medication.Nevertheless, this study has several potential limitations. First, it is a single-center study of an ethnic population that is not diverse. Second, the large size of the dataset used to develop the models reduces the likelihood of overfitting. Third, In summary, we present risk prediction models for estimating the risk for MACEs on the basis of clinical parameters that are commonly available in all patients with MI undergoing PPCI. These models can be implemented alongside further medical investigations to support therapeutic decision-making. However, as with any new risk prediction model, further independent evaluation is required in different settings, including different geographic locations and healthcare organizations, to guide application in clinical management and practice.hbyanfuwai2018@163.com.The data analyzed in this study is subject to the following licenses/restrictions: The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request. Requests to access these datasets should be directed to XZ and HY: conception and design. HY: administrative support. HY, CL, and PZ: provision of study materials or patients. XZ, CL, PZ, ZS, JL, JZ, RC, and YW: collection and assembly of data and data analysis and interpretation. All authors: manuscript writing and final approval of manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Understanding relationships among blood pressure (BP), cognition, and brain volume could inform Alzheimer's disease (AD) management.We investigated Alzheimer's Disease Neuroimaging Initiative (ADNI) participants: 200 controls, 346 mild cognitive impairment (MCI), and 154 AD. National Alzheimer's Co‐ordinating Center (NACC) participants were separately analyzed: 1098 controls, 2297 MCI, and 4845 AD. Relationships between cognition and BP were assessed in both cohorts and BP and atrophy rates in ADNI. Multivariate mixed linear‐regression models were fitted with joint outcomes of BP , cognition  and atrophy rate .P value]; 0.2, 0.005 and 0.2, 0.04, respectively). NACC AD patients with lower systolic BP had lower cognitive scores .ADNI MCI and AD patients with greater baseline systolic BP had higher hippocampal atrophy rates ([r, Higher late‐life BP may be associated with faster decline in cognitively impaired elders. We also investigated BP and cognition in a group of 8240 participants from a complementary dataset: National Alzheimer's Coordinating Center (NACC). We hypothesized that BP would be associated with brain volume change; changes in BP would be associated with changes in brain volume. Similarly, we hypothesized that baseline BP would be associated with baseline neuropsychology and change in neuropsychology. We also considered that BP changes would be associated with changes in neuropsychology.22.12.1.1www.adni-info.org. All participants were from the first phase of the study (ADNI1). All MCI and AD patients had an amnestic impairment. AD patients met criteria for probable AD according to the NINCDS‐ADRDA criteria.http://adni.loni.usc.edu/wp-content/uploads/2010/09/ADNI_GeneralProceduresManual.pdf and section 1.1 in the supporting information. In brief, all ADNI subjects had to be between 55 and 90 years at enrolment, be English or Spanish speaking, and have a partner able to provide an independent evaluation of functioning. Individuals taking specific psychoactive medications were excluded. We included patients enrolled in ADNI1 from September 2005 to 2010. The study schedule consisted of visits at baseline, 6 months, 12 months, 24 months, and 36 months. There were alterations to this schedule for disease groups; MCIs had an additional 18‐month visit and AD participants had their final visit at 24 months.We obtained data from the ADNI database (adni.loni.usc.edu). Data are freely available for qualified researchers. Participants engaged in baseline clinical, neuropsychometric, and magnetic resonance imaging (MRI) assessments and periodical assessments thereafter. Written informed consent was obtained from each participant and approved by the Institutional Review Board at each of the >50 participating centers. ADNI is a multicenter longitudinal private‐publicly funded study launched in 2003 investigating healthy controls, mild cognitive impairment (MCI), and AD participants. Based in America, ADNI is headed by Michael W. Weiner. The principle goal of ADNI has been to test whether use of serial MRI, positron emission tomography (PET), biomarkers, and clinical and neuropsychological data could measure the progression of MCI and early AD. For up‐to‐date information see Systematic review: We reviewed the literature using PubMed. There has been substantial recent interest in the relationships of blood pressure, cognition, and atrophy. The relevant publications have been cited in the manuscript.Interpretation: Our findings demonstrate that potentially modifiable variables are associated with volume change in the brain in clinical Alzheimer's disease (AD). Our results also show there is a need to monitor blood pressure in late life including in individuals with cognitive impairment.Future directions: Further research is required to (a) understand the mechanisms of late‐life hypertension and hypotension in neurodegeneration and cognitive impairment; (b) develop appropriate blood pressure levels for those in old age, and for those elderly with cognitive impairment; and (c) investigate whether stratification of clinical trials for putative AD treatments by blood pressure measurements is useful.2.1.2http://www.alz.washington.edu/), from the March 2014 data freeze. Data are freely available for the research community. NACC has developed and maintains a database of standardized clinical research visits, collected from 39 past and present NIA‐funded Alzheimer's Disease Centers (ADCs) in the United States. The recruitment of participants and data collection in NACC has been described previously.We included participants from the NACC data set . Imaging data were unavailable for the majority of subjects; therefore, for NACC we investigated BP and cognition relationships only. Criteria on MCI diagnosis for ADCs was developed using consensus guidelines set by an expert panel.2.2Seated systolic blood pressure (SBP) and diastolic blood pressure (DBP) readings were measured at all visits for ADNI and at approximately annual visits for NACC (see section 1.2 in supporting information). Pulse pressure (PP) was calculated as SBP minus DBP.2.3The ADNI MRI protocol is detailed elsewhere.2.4We investigated three longitudinal cognition outcomes: Mini‐Mental State Examination (MMSE) for global impairment, Logical Memory Immediate Story Recall (LM) for memory, WAIS‐R Digit Symbol (DSST) for processing speed. Examinations were administered at each visit, apart from LM in ADNI, which was administered annually.2.52.5.1Demographic differences between groups for continuous outcomes were tested using analysis of variance; Fisher's exact test was used for categorical outcomes. TIV was used as a covariate for brain and hippocampal outcomes.2.5.2We jointly modeled change in BP , change in cognition, and change in brain/hippocampal volume. There was no “predictor” as with traditional regression models; to observe concurrent changes in BP, cognition, and atrophy, each of the three variables were jointly modeled as outcomes. Multivariate mixed linear‐regression models were fitted with outcomes of BP , atrophy , and cognition . A random intercept  and random slope were included for the participant level with unstructured covariance to allow for correlations among all random effects, apart from the random intercept for atrophy rate. The atrophy rate random intercept was included to account for the random measurement error at the first scan, which would be shared between all atrophy measures. Likelihood ratio tests were used to test random effects correlations between outcomes. The following correlations were examined: (1) baseline BP, change in brain volume; (2) change in BP, change in brain volume; (3) baseline BP, baseline neuropsychology; (4) baseline BP, change in neuropsychology; (5) change in BP, change in neuropsychology. Models were run separately in each diagnostic group.APOE) ε4 status  was included in the relevant ADNI models to adjust for associations with baseline BP, baseline MMSE, MMSE change, and brain volume change.No fixed effects intercept was included in the model for change in brain volume due to the assumption that the estimated atrophy rate over a scan interval of zero is zero. As no intercept, or measure of baseline volume change, is estimated using BSI (volume change) data, we separately modeled baseline brain and hippocampal volume in a regression model (see below). We used the multilevel modeling software MLWin version 2.36, February 2016 release.Fixed effects data are tabulated in supporting information. Due to lack of any detectable change over time in SBP and DBP for ADNI AD patients the random effect slope for change in blood pressure was removed to allow the model to converge. For PP in the ADNI AD group the random effect slope was permitted, but the random effect correlation between baseline PP and change in PP was omitted.APOEε4 , see section 1.3 in supporting information.For NACC, models were also fitted with adjustment for antihypertensive medication use and also for APOE ε4 status, TIV, and sex were included as covariates.In ADNI, to investigate correlations between baseline BP and baseline whole‐brain/hippocampal volumes, regression models were fitted, with separate outcomes of whole‐brain/hippocampal volume and baseline BP  as the predictor. Age, 2.5.3https://www.nhlbi.nih.gov/health-topics/hypotension). Demographics for groups and fixed effects resulting from the models are tabulated in Table S7 in supporting information.AD patients were categorized by hypertensive status based upon initial BP and antihypertensive usage. BP cut‐offs for hypertension were defined as = >140 mmHg for SBP and/or = >90 mmHg for DBP.For information on figures and tabulation see section 1.4 in supporting information. For reference we ran all graphically presented effects without adjustment for covariates.33.1APOE ε4 carrier than controls . MCI and AD patients had lower brain and hippocampal volumes, greater cognitive impairment, and were more likely to be an A total of 8240 NACC participants were suitable for the present study. Controls were older and were more likely to be female, compared with MCI and AD groups.3.2From both ADNI and NACC, controls on average had no significant change in BP over time (see Table S1 in supporting information). ADNI controls had significant rates of brain and hippocampal volume loss, but did not decline in cognition over time. The larger group of NACC controls had, on average, a decline in MMSE and LM.3.2.1P value); ). However, there were no significant correlations between baseline, or change in, blood pressure and brain/hippocampal volume change over time (Table S3 in supporting information).ADNI control participants with higher baseline DBP had lower baseline brain volumes, see Figure 3.2.2P value)   –0.4, 0.05 . ADNI MCI participants declined in MMSE and DSST over time, but not LM. NACC MCI participants showed significant rates of decline in all neuropsychology measures.3.3.1P value)    Figure , and a sNo correlations were found between BP and neuropsychology in ADNI (see Table S4).3.4The ADNI AD group did not show any significant change over time in BP, but falling SBP, DBP, and PP were all detected in the NACC AD group, see Table 1.3.4.1Higher baseline SBP was associated with greater subsequent hippocampal atrophy 0.23, 0.04) , and the non‐medicated, normotensives . A relationship between low baseline BP and subsequent MMSE decline was found in hypotensive groups . An opposing relationship was found in the hypertensive groups, in which high baseline BP predicted MMSE decline, although only significantly in the non‐medicated group despite equal effect sizes . Last, both hypertensive groups showed simultaneously falling BP and falling MMSE . There were no relationships between BP and cognition in the medicated normotensives, despite being the largest group.We found low baseline BP predicted low baseline MMSE in the medicated hypotensives . With adjustment for antihypertensive usage in NACC (Table S6 in supporting information) all relationships remained unchanged, apart from the correlation between declining SBP and PP and falling MMSE in AD, which was no longer significant.With adjustment for Graphically represented results were also tested without adjustment for covariates and the majority of findings were materially unchanged  in clinically defined AD. More work is required to understand whether lowering of BP can attenuate progression in hypertensive cognitively impaired individuals. For clinical trials targeting AD pathology, increased power to detect a treatment effect may be achieved by stratifying or adjusting for BP. Last, in AD, both hypertension and hypotension may accelerate disease course, and therefore BP should be carefully monitored.There are no reported conflicts apart from a note that Christopher Lane is now employed by Eisai Europe Ltd.The Dementia Research Centre is supported by Alzheimer's Research UK, Brain Research Trust, and The Wolfson Foundation. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit and the National Institute for Health Research Biomedical Research Centre (BRC). CF and JB are supported by Alzheimer's Research UK; Alzheimer's Research UK Senior Fellowship (ARUK‐SRF2016A‐2). Christopher Lane was funded by an MRC DPUK grant.www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.Data collection and sharing for this project was funded by the (ADNI)  and DOD ADNI (Department of Defense award number W81XWH‐12‐2‐0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‐Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‐La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health , P30 AG013846 , P50 AG008702 , P50 AG025688 , P50 AG047266 , P30 AG010133 , P50 AG005146 , P50 AG005134 , P50 AG016574 , P50 AG005138 , P30 AG008051 , P30 AG013854 , P30 AG008017 , P30 AG010161 , P50 AG047366 , P30 AG010129 , P50 AG016573 , P50 AG005131 , P50 AG023501 , P30 AG035982 , P30 AG028383 , P30 AG053760 , P30 AG010124 , P50 AG005133 , P50 AG005142 , P30 AG012300 , P30 AG049638 , P50 AG005136 , P50 AG033514 , P50 AG005681 , P50 AG047270 .Supporting Information.Click here for additional data file.