The dogma that urine is sterile in healthy individuals has been overturned by recent studies applying molecular-based methods. Mounting evidences indicate that dysbiosis of the urinary microbiota is associated with several urological diseases. In this study, we aimed to investigate the urinary microbiome of male patients with calcium-based kidney stones and compare it with those of healthy individuals.P < 0.001 for both indices). The urinary microbiota structure also significantly differed between kidney stone patients and healthy controls . Differential representation of inflammation associated bacteria  and several enriched functional pathways were identified in the urine of kidney stones patients. Meanwhile, we found the species diversity, overall composition of microbiota and predicted functional pathways were similar between bladder urine and renal pelvis urine in kidney stone patients.The diversity of the urinary microbiota in kidney stone patients was significantly lower than that of healthy controls based on the Shannon and Simpson index (A marked dysbiosis of urinary microbiota in male patients with calcium-based kidney stones was observed, which may be helpful to interpret the association between bacteria and calcium-based kidney stones. Nephrolithiasis is a common urological disorder worldwide, with a prevalence of 5–20% in different geographic regions and a recurrence rate of 50% at 10 years of follow-up . SimilarOxalobacter formigenes, an oxalate degradation bacterium, was reported to be negatively associated with urinary stones and reduce urinary oxalate excretion when administered orally as a probiotic [O. formigenes, ranging from 0 to 100% in kidney stone formers and 11–100% in individuals with no history of nephrolithiasis [O. formigenes have been disappointing so far [The term human microbiome is defined as all genetic materials of micro-organisms existing in different regions of the body. In the past few years, the role of gut microbiome on urine oxalate excretion and kidney stone formation has been a hot issue. Early study identified distinct gut microbiome and enrichment of oxalate metabolizing bacterial species in nephrolithiasis patients . Oxalobarobiotic . DespiteThe urinary microbiome, identified in healthy individuals, is associated with several urologic diseases such as incontinence, genitourinary cancer and urinary tract infection , 13. EarIn the present study, we utilized 16S rRNA gene sequencing to characterize the urinary microbiome potentially associated with calcium-based kidney stones. The aim of our research was to (1) determine if the microbiome of bladder urine is significantly different between kidney stone formers and healthy individuals; (2) determine if the microbiome of bladder urine is distinct from that of renal pelvis urine in nephrolithiasis patients. (3) predict functional pathways that significantly enriched in the urinary microbiome of kidney stone formers.Urine samples were collected from a total of 43 subjects, and the demographic and clinical data was listed in Table P = 0.046).In total, 5,906,796 clean reads were obtained from the 65 urine samples. The median number of reads in kidney stone patients was 94,966 and in healthy controls was 126,090. The reads were classified into 928 unique operational taxonomic units (OTUs) at 97% similarity level that were used for downstream analysis. We defined three groups according to the kidney stone status and specimen-type: HB represents bladder urine collected from healthy controls, KB represents bladder urine from kidney stone patients, while KP represents renal pelvis urine from kidney stone patients. The HB group showed the largest amount of OTUs, and there was substantial overlap in the OTUs composition among HB, KB and KP groups . The α − diversity of urinary microbiota between KB and KP group was also evaluated, and all indices showed no significant difference. For β − diversity, we applied unweighted and weighted principal coordinate analysis (PCoA) to display discrepancy among the three groups. It showed that KB and KP samples clustered closer in proximity to each other than HB samples , while the microbiota structure between KB and KP groups was similar .For α − diversity, the values of Good’s coverage index of all libraries were above 99%. The α − diversity indices, including observed species, chao 1 index, ACE index, Shannon diversity index, of the microbiota in HB group were all higher than those of KB group Fig. . Moreoveles Fig. . We furtp = 0.01) and a lower average representation of Firmicutes  and Bacteroidetes . Significant abundance differences of numerous taxa were also noted between KB and HB groups at other taxonomic levels  and lower average representation of Fusobacterium  was observed in KP group at genus level.Of interest, we also analyzed the microbiota of paired bladder urine and renal pelvis urine collected from kidney stone patients. At phylum or class level, the overall bacterial compositions of KB and KP groups were quite similar Fig. a-b. HoweP < 0.05 in Wilcoxon test were considered differentially represented. LEfSe identified 31 discriminative features with significant different relative abundance among HB, KB and KP groups  score more than 2.0 and Having observed a distinct urinary microbiota in kidney stone patients, we further evaluated whether the different bacterial community was associated with specific alterations involved in metabolic processes. The functional pathways of urinary microbiome in HB, KB and KP samples were inferred using PICRUSt tool. Compared to HB group, the significantly enriched KEGG pathways in KB groups included proximal tubule bicarbonate reclamation, ion channels, linoleic acid metabolism and renin−angiotensin system  differentially represented in KP group, remaining an area for future research.Another important finding in this study was the similarity of overall bacterial composition between bladder urine and renal pelvis urine in kidney stone patients. Traditionally, bacteria are considered to access the upper urinary tract under certain conditions, such as urinary reflux or bacteria translocation in severe systemic disease. However, a preliminary study showed bacteria could be detected in the upper tract urine of kidney stone patients without urinary tract infections . Due to Some limitations should be noted when interpreting our results. First, all participants were Chinese and the sample size is relatively small, limiting generalizability and comparison of stone subtypes. Further largescale studies are necessary to investigate the urinary tract microbiota across ethnicity and stone type. Second, this study did not include female subjects, mainly due to their lower morbidity of kidney stones and higher positive rate of urine routine tests. In the future, we will conduct a more comprehensive research after recruiting adequate females in line with our inclusion criteria. Additionally, the association of risk factors for lithogenesis in urine and urine microbiota was not evaluated, because the vast majority of kidney stone patients were first onset and 24 h urine analyses were not performed. Finally, like most metagenomic studies, we cannot comment as to whether altered urinary microbiota in kidney stone patients was a contributor or the result of kidney stone formation. All these questions will certainly be the focus of future research.In conclusion, our study revealed distinct urinary microbiota in male kidney stone patients compared to healthy individuals, and similar microbiota between bladder urine and renal pelvis urine. Several predicted functional pathways and bacteria associated with inflammation were found to differentially represent in the urinary tract of kidney stone patients. We speculated that bacteria might influence the formation of calcium-based kidney stones via modulation of inflammatory processes. Our findings may provide useful information to interpret the association between bacteria and calcium-based kidney stones.We recruited a total of 43 adult males, including 22 kidney stone formers and 21 age-matched healthy volunteers at Shenzhen People’s Hospital. All nephrolithiasis patients were diagnosed by ultrasonography, abdominal plain film, intravenous pyelography or computed tomography, and kidney stones were confirmed during endoscopic surgery. The chemical composition of surgically removed stones was analyzed by infrared spectroscopy.In order to control the confounding factors that might affect urinary microbiome, we set strict exclusion criteria. For healthy controls, exclusion criteria included personal history of urinary stones, episodes of renal colic or imaging confirmed urinary stones. All healthy controls underwent ultrasonography to confirm the lack of asymptomatic renal calculus. For kidney stone patients, exclusion criteria included struvite stones, concurrent ureteral calculus, moderate to severe hydronephrosis, and ureteral stent or catheter placement before sample collection. Excluded from both groups were subjects using antibiotic within 30 days, with urinary tract infections or positive urine culture, congenital abnormalities of the urinary tract, history of major urological surgery, diabetes with poorly controlled glucose, autoimmune disease, chronic kidney disease with blood creatinine > 1.4 mg/dL and age (< 20 years or > 70 years old).Bladder urine samples were obtained by transurethral catheterization from all participants. For nephrolithiasis patients, paired renal pelvis urine samples were collected on the side of kidney stones via ureteral catheter using aseptic technique, prior to surgery or ureteral stent insertion. Before the renal pelvis urine collection, the bladder was voided by catheter with an attempt to control the mixture of bladder urine. All samples were collected prior to antibiotic use and stored in sterile containers at − 80 °C within 1 h from collection. The volume of each urine sample was approximately 12 ml and the time for renal pelvis urine collection was approximately 10 min.Prior to DNA extraction, all samples were centrifuged 12,000 g for 10 min at 4 °C. Pellets were re-suspended and mixed with DNA-free phosphate buffered saline. Genomic DNA was extracted from all samples using DNeasy PowerWater Kit . Integrity of DNA was verified with agarose gel electrophoresis and the DNA concentration was quantified by Qubit® 2.0 Fluorometer . All DNA extractions were stored at − 20 °C until further processing.The V3-V4 region of the 16S rRNA gene was amplified by polymerase chain reaction with primers shown as follows: V3-V4-341F: 5′- CCTACGGGNGGCWGCAG-3′ and 907R: 5′-TACNVGGGTATCTAATCC-3′. Polymerase chain reaction was performed using the following conditions: 3 min denaturation at 98 °C; 30 cycles of denaturation at 98 °C for 45 s, annealing at 55 °C for 45 s, elongation at 72 °C for 45 s; and final extension at 72 °C for 7 min. The amplicons were purified by the AMPure beads , and barcoded libraries were sequenced on the Illumina Hiseq2500 platform. Sterile phosphate buffered saline with and without bullet blender beads were used as negative controls during processing.Raw sequencing data was pre-processed to eliminate low-quality reads and adapter pollution by using Mothur . Clean rFor α − diversity, observed species, chao 1 index, ACE index, Shannon index, Simpson index and Good-coverage index were calculated by Mothur. For β − diversity, both unweighted and weighted UniFrac distances were conducted using QIIME and shown by the PCoA . Analysip values < 0.05 as statistically significant. Clinical categorical variables were compared using Pearson’s chi-square test or Fisher’s Exact Test, while continuous variables were analyzed via a student’s t test. Age and body mass index were expressed as mean ± standard deviation. For α-diversity and taxonomic analysis, Wilcoxon rank-sum test or Kruskal-Wallis test were performed with R software. For β − diversity, statistical comparisons of weighted UniFrac distances were conducted by ANOSIM using the vegan package of R software.Statistical analyses were performed with the SPSS (version 21.0) and R software (version 3.4.1), considering Additional file 1: Figure S1. Microbial pathways that were significantly differentially enriched between HB and KB groups.Additional file 2: Figure S2. Predicted microbial pathways were not significantly differentially represented between KB and KP groups.


Asthma is one of the most common diseases amongst children. Blood eosinophil count and neutrophil–lymphocyte ratio (NLR) are known as markers for phenotyping asthma. This study was performed to investigate blood eosinophil count and NLR as predictors of hospitalization in pediatric asthma exacerbations.In this cross-sectional study, children admitted to hospital ward for more severe asthma exacerbation were compared with non-hospitalized children with moderate to severe asthma exacerbation whose asthma exacerbation was managed in emergency department or outpatient clinic. We investigated patients’ characteristic and factors associated with hospitalization.P = 0.027), a blood eosinophil count P < 0.001) and an NLR P = 0.027) were associated with hospitalization.A total of 211 children with moderate to severe asthma exacerbation (mean age Blood eosinophil count and NLR were found to be higher in hospitalized children with more severe asthma exacerbation compared to non-hospitalized patients. These markers can be indicators for asthma exacerbation severity. Since in hospitalized children with asthma exacerbation, blood eosinophil count and NLR were observed to be higher than non-hospitalized ones, these markers can help predicting hospitalization in paediatric patients with asthma exacerbation.Asthma is one of the most common chronic disease in children . AccordiAsthma is a chronic inflammatory disease of the airways that has different clinical and immunological phenotypes. To date, two cluster analyses were done in Severe Asthma Research Program (SARP) for characterization of different presentations of severe asthma. The first cluster analysis included clinical and physiologic parameters , while bronchoscopic and inflammatory data  were main variables of the second one. Different phenotypes like early onset asthma, allergic asthma  with an inflammatory process in severe types were recognized in both analyses , 5. EvidAsthma exacerbation is a worsening in condition of a patient with stable asthma, which is mostly caused by viral infection , and hosNeutrophil–lymphocyte ratio (NLR) can indicate systemic inflammation. Mean NLR increases in asthma patients especially in those with unstable asthma compared to healthy subjects , 18. RegBased on guidelines of the Expert Panel Report 3 (EPR-3), severity of an asthma exacerbation is determined by signs and symptoms such as respiratory distress, dyspnea, Initial Peak Expiratory flow (PEF), oxygen saturation, and clinical course. Furthermore, patients with severe respiratory distress, low oxygen saturation and not responsive to primary care with oxygen, beta-agonists, and systemic glucocorticoids should be admitted in hospital ward .To the best of our knowledge, there is no study simultaneously evaluating blood eosinophil and NLR in asthma exacerbation. Thus, the present study was conducted to investigate these markers as biomarkers of asthma exacerbation severity and specifically as contributing factors for hospital admission.We carried out a retrospective cross-sectional study on children aged less than 18 years old with moderate to severe asthma exacerbation classified based on Expert Panel Report 3  and refeData on patients’ demographic characteristics e.g. age, gender, complete blood count, white blood cell differential; and hospital course e.g. duration of admission, comorbidity, antibiotic consumption were collected , while mean and standard deviation were used to present continuous values. Cross-sectional administrative data were analysed in a case control manner. Data were compared in hospitalized patients with non-hospitalized patients, and comparisons were also made in hospitalized patients in terms of blood eosinophil counts and NLR levels. Statistical analyses were done using receiver operating characteristic (ROC) Curve, ANOVA, Chi-Squared, Fisher’s exact test, Wilcoxon-signed rank, Mann–Whitney U, or Independent Samples T-tests as appropriate. Spearman’s correlation coefficient was used for assessing correlations between the variables. A binary logistic regression model was applied to determine the predictors of hospitalization in asthma exacerbation. The variables with a Categorical variables were addressed by P = 0.020). Newly diagnosed asthma was significantly higher  and using a written action plan before exacerbation was significantly lower  among hospitalized patients.In this study, 28 out of 239 cases were excluded due to concomitant disorders and long-term corticosteroid use. 211 patients with moderate to severe asthma exacerbation  with mean age of P < 0.001). Mean hospital admission days were During hospitalization course, antibiotics were prescribed for 55 cases (60.4%) of hospitalized patients. Among which, 47 cases (85.4%) received at least one dose of parentral antibiotic, 20 cases (36.7%) received oral macrolides and 17 patients (30.9%) received both parentral and oral antibiotics. Antibiotic therapy was significantly higher in hospitalized patients  in hospitalized patients, while there was a significant positive correlation between NLR and age (P < 0.001).In hospitalized patients with an NLR < 2.52, the age was significantly lower than patients with a higher NLR (P = 0.027), a blood eosinophil count P < 0.001) and an NLR P = 0.027) are significant factors predicting hospitalization in patients with asthma exacerbation  was associated with hospital admissions. Previous studies have investigated on blood eosinophil count in asthma patients using different methods. 3 studies conducted in United Kingdom (UK) and United States (US) strongly supported the increase in blood eosinophil counts In this study, a blood eosinophil count rbations , 15, 26.rbations  and Makerbations  have shorbations  in a retchildren , 29. Higchildren .P = 0.027). NLR is a marker of inflammation and paediatric asthma exacerbations are mostly triggered by viral infections causing airway inflammation, and this explanation is in line with our finding. Machimaro, et al. [In our study, occurrence of more severe asthma exacerbations leading to hospitalization was found to be associated with higher NLR . Parents of children with asthma should be educated about the disease, the medications and proper way to use them, and what to do in an emergency. Previous studies [Another finding of this study was the association of not using an asthma action plan with hospital admissions (OR 2.22, 95% CI 1.09–4.49;  studies , 31 showResults of the current study showed a positive correlation between age and NLR (rly ages , this corly ages  showed aNacaroglu et al.  in a stuHuang et al.  and alsoOur results indicated that, antibiotic therapy had a significantly higher percentage among hospitalized patients (60.4% vs. 19%, de issue , 38 contThere were some limitations in our study. Main limitation was that, there was not any significant data about phenotypes of asthma in Iran and they were not checked in our patients before or after the exacerbations. Study on presence of eosinophil and NLR in bronchial system is more accurate and reliable compared to their presence in the blood, which can be considered for further studies especially regarding phenotyping of asthma.Blood eosinophil count and NLR were found to be higher in the patients hospitalized due to asthma exacerbation. These markers can be predictors for hospitalization in asthma exacerbations in addition to clinical judgment.Additional file 1. Patients' data on demographic characteristics and laboratory findings.


The placenta accreta spectrum (PAS) is a severe complication of pregnancy and is associated with massive haemorrhage, hysterectomy, and even perinatal maternal-foetal death. Prophylactic abdominal aortic balloon occlusion (PAABO) is a novel and efficient therapy for these patients. The aim of this study was to investigate the benefits, potential risks, and characteristics of anaesthesia management.n = 25) received PAABO, and Group B (n = 23) underwent a normal operative procedure. The characteristics of the general parameters, anaesthesia, and operative procedure were noted. Data on vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) during the operation were recorded. Before and after the procedure, hepatic and renal function and lactate dehydrogenase (LDH) were also measured.A total of 48 parturients with PAS were enrolled and divided into two groups. Group A  were observed in both groups, and increased glutamic-pyruvic transaminase (GTP) was observed in Group B.PAABO reduced perioperative blood loss and the risk of hysterectomy among parturients with PAS. Sophisticated anaesthetic management should be implemented to prevent or reduce perioperative complications and address internal disorders that are caused by massive blood loss. The placenta accreta spectrum (PAS) is a severe complication of pregnancy and is associated with massive haemorrhage, hysterectomy, and even perinatal maternal-foetal death. The PAS can be divided into three types according to the depth of implantation: placenta accreta, placenta increta, and placenta percreta . ParturiRadiation-guided endovascular interventional techniques for the treatment of obstetric haemorrhage have emerged over the past 30 ~ 40 years , includiHowever, although several articles have reported the haemostatic effect and safety of PAABO, little is known about the perioperative changes and characteristics of anaesthesia management. In the present study, we retrospectively investigated the benefits, potential risks, and characteristics of anaesthesia management with PAABO.We performed a historical control study of patients with PAS from 1st March 2015 to 30th September 2016 in the Maternal and Child Care Hospital of Anhui Province. Written informed consent was obtained from each parturient before enrollment in the study according to the process of informed consent by the Institutional Ethics Committee of Anhui Women and Child Health Care Hospital. The study was approved by the Institutional Ethics Committee of Anhui Women and Child Health Care Hospital (2016(12)).Forty-eight pregnant women were included in this trial, and the inclusion criteria were as follows:(1) clinical diagnosis of PAS by US or MRI; (2) gestational age > 31 weeks; and (3) elective or emergency caesarean delivery. The exclusion criteria were refusal by the parturient, antepartum bleeding, severe cardiac disease, aortic diseases and lack of complete information. The parturients were divided into two groups. Group A comprised 25 patients who underwent PAABO before CS. Group B comprised 23 patients who were not treated with PAABO: 10 did not undergo PAABO because they were hospitalized before October 2015, during which the PAABO technique was not available, and 13 declined the procedure.P < 0.05 was deemed to indicate a statistically significant difference.In our pilot study, we found that compared with baseline values, the mean SBP level was elevated by 16.43 mmHg in Group A and 2.26 mmHg in Group B at T2 . The standard deviations were 10.39 and 9.46, respectively. To achieve 90% power for the test, a minimum sample size was calculated by G*Power 3 [For Group A, the prophylactic abdominal aorta balloon was implemented by the radiologist in a DSA operating room. The right femoral artery was punctured using a modified Seldinger technique. A 12-F sheath was inserted from the femoral artery to the infrarenal abdominal aorta. The 8-F pigtail occlusion balloon catheter was embedded and located below the level of the renal artery.After foetal delivery and umbilical cord clamping, the balloon was inflated with 6 ~ 15 ml 0.9% saline solution if the placenta could not spontaneously be expelled or severe bleeding was present. Complete occlusion was defined as absent pulsation of the dorsalis pedis artery and a foot oxygen saturation of 0 . The lonIn Group B, patients underwent CS and placenta evacuation without balloon occlusion of the abdominal aorta, followed by uterine artery ligation, local excision of the uterine wall, bladder repair, and even hysterectomy according to the placenta accreta location and depth. The intramuscular injection of uterotonic drugs ( 20 U of oxytocin and 100 µg of carbetocin or 250 µg of tromethamine) was given immediately after delivery of the baby and clamping of the umbilical cord.2), electrocardiogram (EKG), invasive arterial blood pressure (IBP), central venous pressure (CVP), and arterial blood gas analysis, were monitored in all parturients.Regarding the anaesthesia procedure, 24 parturients in Group A and 3 parturients in Group B were operated under general anaesthesia. General anaesthesia was performed with propofol (1.5 mg/kg), remifentanil (1.5 mg/kg), and succinylcholine (1.5 mg/kg) followed by tracheal intubation and mechanical ventilation just before skin incision. Midazolam (2 mg), sufentanil (0.3 µg/kg), and cisatracurium (0.15 mg/kg) were added after foetal delivery. Continuous pumping of propofol (6 mg/kg/h) and remifentanil (2 µg/kg/h) was performed to maintain the depth of anaesthesia. One parturient in Group A and 20 parturients in Group B were administered combined spinal and epidural anaesthesia. The patient’s vital signs, including blood oxygen saturation (SPOThe primary outcomes were estimated blood loss (EBL), blood transfusion volume, incidence of hysterectomy, change in haemoglobin level after surgery, and vital parameters during surgery. EBL was calculated with the collection of blood in the suction bottle and the weight of the surgical swabs, subtracting the volume of amniotic fluid. Data on vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were recorded at baseline (T0), 1 min before balloon inflation (T1), 1 min after balloon inflation (T2), 5 min after inflation (T3), 1 min after deflation (T4), and 5 min after deflation (T5).The secondary outcomes included the operating time from the time of skin incision to skin closure, the balloon occlusion time, maternal balloon occlusion-related complications, neonatal outcomes including Apgar scores at 1 and 5 min, and a comparison of the outcomes in general anaesthesia versus regional anaesthesia.t-tests. Abnormally distributed data, such as the volume of red blood cells transfused, were analysed using the Mann-Whitney U test. Categorical variables, such as hysterectomy, neurologic complications of the lower limbs, and gastrointestinal complications, were assessed using Fisher’s exact test. For laboratory data, paired t-tests were used to compare the preoperative and postoperative values, and two-sample t-tests were used to compare data from the two groups. Vital parameters including SBP were analysed by repeated measures ANOVA. P < 0.05 was considered statistically significant.Continuous variables were expressed as the mean ± standard deviation. Categorical variables are described as numbers and percentages. Data were analysed by using SPSS version 16.0. Normally distributed data, such as demographic data, EBL, change in haemoglobin levels and operating time, were analysed using independent samples According to the guidelines for treatments of PAS, a total of 40 parturients were implanted abdominal aorta balloon prophylactically but only 25 balloons ultimately needed to be inflated. Data in this study were recorded for all 48 parturients with 25 cases of PAABO and 23 cases of non-treatment with PAABO. The demographic and obstetric characteristics of the parturients were comparable, and are shown in Table P = 0.046, Table P = 0.006, Table y was performed in 2 cases in Group A and 4 cases in Group B  and upper gastrointestinal stress ulcer (1 in Group A with a bleeding volume of 800 ml), which were totally found in 14 cases  with regional anaesthesia (RA), the time from skin incision to delivery, operative duration, EBL, and Apgar scores were collected Table . The resIn this study, we found that balloon occlusion could reduce EBL and the ratio of EBL ≥ 1000 ml. Here, in patients with PAS, PAABO was confirmed to have more advantages in reducing blood loss during caesarean delivery than traditional interventional therapies. These results were consistent with previous research .In response to this novel technology, it is imperative for anaesthesiologists to be familiar with the physiologic changes induced by balloon inflation and deflation to conduct appropriate anaesthetic methods and to address massive haemorrhage. Until now, few reports have addressed the points about anaesthetic management. Anaesthesiologists’ goal is to develop an appropriate anaesthesia regimen with no adverse effects on women and babies, to minimize fluctuations during operative haemodynamics, to address haemorrhagic events, and to prevent perioperative complications .Anaesthesia for CS with PAS remains controversial. Regarding the potential impact of anaesthesia on babies, the preferred anaesthetic method for CS is regional anaesthesia . HoweverThe results showed that arterial blood pressure was significantly elevated after balloon inflation, which was consistent with the report by Xin Wei . A modesComplications are the most important features that anaesthesiologists need to focus on with regard to PAABO. The relevant complications include embolization of the lower extremities , ischaemThe present study had several limitations. First, it was a retrospective and single-centre study, in which there was a lack of randomness in grouping, leading to selection bias. Second, the sample size was relatively small, which might lead to a less statistically powerful sample and unstable and inaccurate results. Third, we compared the effect of GA with RA in all patients with PAS rather than those with PAABO, resulting in some defects of imbalance and incompletion. Finally, the depth of the study is insufficient, and some indexes such as lactic acid could have been affected by inflation balloon. Therefore, a prospective and multicentre study with more patients is needed.PAABO reduced perioperative blood loss and the risk of hysterectomy in parturients with PAS. Sophisticated anaesthetic management should be implemented to minimize adverse effects on mothers and babies, to prevent or treat perioperative complications, and to address gastrointestinal disorders caused by massive blood loss. The management mode of multi-disciplinary team cooperation was very necessary for successful treatment with PAS and PAABO .


The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by 31phosphorus- and 1proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.Oxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances  were significantly higher (5.1 ± 1.1 vs. 3.4 ± 0.7 μmol/L,  Reduced whole-body aerobic capacity in particular, characterized by a lower peak oxygen uptake (peak VO2) and lower VO2 at anaerobic threshold (AT VO2), is known as an independent predictor of all-cause mortality in CHF patients3. Among the various contributors to exercise tolerance, skeletal muscle function is a major determinant of the whole-body aerobic capacity as the skeletal muscles are the largest energy production sites during exercise. We and others have shown that abnormal skeletal muscle energy metabolism is responsible for the exercise intolerance in patients with CHF6.Exercise intolerance is a cardinal symptom of chronic heart failure (CHF), leading to increased morbidity and mortality as well as a poor quality of life9. However, the NYHA functional class is a subjective estimation of a patient's functional ability, and it is thus necessary to determine the roles and effects of systemic oxidative stress with a more objective estimation of functional capacity.Oxidative stress is generally caused by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense capacity. Systemic oxidative stress has been shown to have prognostic value and is associated with heart failure (HF)-related symptoms evaluated by the New York Heart Association (NYHA) functional class in CHF patientsWe conducted the present study to determine whether systemic oxidative stress evaluated by serum lipid peroxidation products and the antioxidant defense capacity is associated with lower whole-body aerobic capacity and with impaired skeletal muscle energy metabolism in patients with CHF.2 and the AT VO2 were significantly decreased in the CHF group compared to the control group, indicating lower whole-body aerobic capacity in the CHF patients.The baseline characteristics of the CHF and control groups are summarized in Table p < 0.01)   were significantly higher , and the workload (20% 1RM) of plantar-flexion exercise was set in each participant. In the 31phosphorus (31P)-MRS study, the standardized phosphocreatine at rest (PCrrest) in the calf muscle was comparable between the CHF and control groups. However, the standardized PCr level at the lowest during the plantar-flexion exercise (PCrlowest) was significantly reduced in the CHF group, and as a result, the muscle PCr loss during the exercise was significantly greater in the CHF cohort, indicating impaired intramuscular high-energy phosphate energy metabolism in the CHF patients. In the 1proton (1H)-MRS study, the intramyocellular lipid (IMCL) content in the resting leg muscle was significantly increased in the CHF cohort, indicating impaired fatty acid metabolism in the skeletal muscle of the CHF patients.The magnetic resonance spectroscopy (MRS) data are summarized in Table 2 and the AT VO2 were inversely correlated with the serum TBARS level, whereas these two parameters were positively correlated with the serum SOD activity in the series of all participants  in the CHF patients, but not with the patients' serum TBARS levels.The peak VOIn the series of all participants, the muscle PCr loss during the plantar-flexion exercise had a positive correlation with the serum TBARS level and an inverse correlation with the serum SOD activity Fig. A. The IM2 and the AT VO2 was decreased, and the skeletal muscle energy metabolism evaluated by the muscle PCr loss during exercise and the IMCL content was impaired in the CHF patients. Notably, both the higher serum TBARS and the lower serum SOD activity were linked to either impaired maximal and submaximal aerobic capacity  or impaired intramuscular high-energy phosphate metabolism . In addition, the higher serum TBARS levels were linked to accumulated IMCL content in the leg muscle. This study is the first to reveal associations between systemic oxidative stress and both exercise intolerance and skeletal muscle abnormalities in patients with CHF.The results of our analyses demonstrated that CHF patients had higher serum TBARS and lower serum activities of SOD, indicating increased systemic oxidative stress in CHF. The whole-body aerobic capacity characterized by the peak VO10. Previous studies have shown that several circulating oxidative stress markers may predict adverse clinical events including all-cause death and hospitalization in CHF patients11. Because exercise intolerance is related to the morbidity and mortality of CHF patients, our present findings of associations of systemic oxidative stress with lowered whole-body aerobic capacity and impaired skeletal muscle energy metabolism may contribute to the understanding of the potential roles and effects of enhanced systemic oxidative stress in the progression of heart failure.Systemic oxidative stress is reported to play a crucial role in disease progression in patients with CHF15. The evidence of an increased number of ROS-loaded blood cells in the coronary sinus compared to that in the peripheral veins in patients with CHF suggests an increased rate of circulating blood cells exposed by myocardial ROS when they pass through the heart16. Indeed, we have observed that mitochondrial ROS in circulating blood cells were elevated in symptomatic CHF patients in relation to systemic oxidative stress10.There are some possible mechanisms by which systemic oxidative stress is enhanced in CHF patients. First, excessive ROS production in a failing heart may increase the level of circulating free radicals. Clinical and experimental studies have demonstrated enhanced ROS production and oxidative stress in the failing heart18. We also demonstrated that one-leg immobilization for 2 weeks induced excessive ROS production accompanied by impaired mitochondrial respiratory capacity in the immobilized leg muscles of humans19. Accordingly, physical inactivity as well as the intrinsic impairment of skeletal muscle function under the condition of CHF seems to contribute to greater ROS production in the skeletal muscles, leading to the enhanced systemic oxidative stress in CHF patients.Second, skeletal muscles can be a source of ROS in CHF, which supports the hypothesis that increased myocellular ROS directly impair skeletal muscle energy metabolism. We and others have shown that HF-model rodents had enhanced mitochondrial oxidative stress in their skeletal muscle20. Although we did not evaluate the participants' daily physical activity in the present study, exercise intolerance can induce a poor quality of life with a reduction of physical activity, which may result in lowered serum SOD activity in CHF patients. Further studies are needed to clarify the mechanisms underlying the enhanced systemic oxidative stress in CHF patients.Finally, physical inactivity itself may reduce the body's systemic antioxidant defense capacity31P-MRS. The PCr is an important energy source and works as an energy buffer, because the PCr can be promptly converted into ATP to maintain the ATP at a constant level during exercise. Since exercise with the load of 20% 1-RM is low-intensity exercise without a decrease in muscle pH , our finding that the muscle PCr loss during the plantar-flexion exercise was increased in the CHF patients might indicate impaired muscle oxidative metabolism.We investigated skeletal muscle energy metabolism by using MRS, which is a well-validated and noninvasive method. We measured the PCr loss in the calf muscle during the plantar-flexion exercise with the constant load of 20% 1-RM to assess the intramuscular high-energy phosphate metabolism using 1H-MRS. The IMCL content is commonly defined by an imbalance between the uptake of fatty acids into the muscle and the intramuscular fatty acid oxidation. In this study, the free fatty acid levels were comparable between the CHF patients and control subjects, and thus the accumulated IMCL in the CHF patients might be attributable mainly to the impaired fatty acid oxidation in the skeletal muscle.We also measured the IMCL content in the resting leg muscle by 21. It has been shown that exercise training improves skeletal muscle function and augments systemic and intramuscular antioxidant capacity in patients with CHF22. Accordingly, exercise training may be beneficial for the restoration of the redox balance as well as the improvement of cardiorespiratory fitness in these patients.Heart failure-related myopathy characterized by impaired skeletal muscle energy metabolism and altered muscle structure  is a major contributor to the exercise intolerance of CHF patients2 when we analyzed only the data of the CHF patients. Because the range of parameters of exercise capacity and skeletal muscle energy metabolism within the CHF group was small, we could not detect a significant correlation. Third, we could not identify the causality of the relationships between systemic oxidative stress and exercise intolerance or skeletal muscle dysfunction. Further studies with larger numbers of participants are necessary to clarify the causal relationships among these parameters.There are some study limitations to consider. First, the number of participants was small (n = 30). Second, the correlations between systemic oxidative stress and exercise intolerance or impaired skeletal muscle energy metabolism were not significant except for the correlation between the serum SOD activity and peak VOIn summary, this study demonstrated for the first time that systemic oxidative stress was related to exercise intolerance and skeletal muscle abnormalities in patients with CHF. Our findings suggest that restoration of the redox balance is beneficial in the treatment of CHF.23 and 13 age-matched healthy subjects as a control group. We excluded patients who had difficulty performing maximal exercise due to a physical problem including orthopedic disease, stroke, severe pulmonary disease, and peripheral artery disease, and patients with diabetes or severe chronic kidney disease. Patients who had been assessed as being NYHA functional class IV were also excluded. The present report is part of an MRS study targeting lifestyle disorders and cardiovascular diseases, and thus some of the data used herein were obtained from the same patients whose data were published previously but in a different context4. The protocol was approved by the Medical Ethics Committee of Hokkaido University Hospital, and written informed consent was obtained from each participant before the study. All investigations conformed to the principles outlined in the Declaration of Helsinki.Thirty male participants were recruited at Hokkaido University Hospital: 17 stable CHF patients who had a history of hospitalization due to worsening HF defined by the Framingham Criteria1H-MRS study to measure the IMCL content in the resting leg muscle. The participants also underwent cardiopulmonary exercise testing (CPET) to assess their exercise capacity. On another day, a 31P-MRS study was conducted to assess the high-energy phosphate metabolism in the calf muscle during plantar-flexion exercise.The participants underwent blood tests for the analyses of blood biochemistry and systemic oxidative stress after a 10-h overnight fast, followed by clinical and anthropometric measurements, echocardiography, and a 24. To assess systemic oxidative stress, we measured the serum TBARS and the enzymatic activity of SOD by conducting fluorometric analyses in all participants as described25.Fasting blood glucose, plasma insulin, HbA1c, HDL-cholesterol, LDL-cholesterol, triglyceride, and free fatty acids were measured in all participants, and the plasma levels of brain natriuretic peptide (BNP) were measured in only the CHF patients by routine in-house analyses. The HOMA-IR was calculated as described26. The left ventricular ejection fraction (LVEF) was measured from apical four- and two-chamber images using the biplane method of disks.Cardiac function was evaluated by echocardiography in the CHF patients as described28. A respiratory gas analysis was simultaneously performed with a breath-by-breath apparatus . The peak VO2 was defined as the VO2 attained at the maximal point during symptom-limited incremental exercise . The AT VO2 was determined by the V-slope method by at least two CPET experts.The participants performed cardiopulmonary exercise testing (CPET) using an upright bicycle ergometer  with a ramp protocol (10–25 watts/min) as described28. After a ≥ 30-min rest, the high-energy phosphate metabolism in the calf muscle was measured during plantar flexion exercise in the supine position on the original apparatus equipped with a 1.5-T whole-body scanner system  using 31P-MRS as described28. The exercise protocol was a constant load of 20% 1-RM at the pace of 40 times/min for 4 min. Usually, immediately after the initiation of the plantar-flexion exercise, the PCr level in the calf muscle started to decrease and was finally stabilized within a few minutes. The PCr was standardized as [PCr] / ([PCr] + [Pi]) on the basis of the notion that [PCr] + [Pi] is constantly equal both at rest and during exercise, where [PCr] indicates the concentration of PCr and [Pi] indicates the concentration of inorganic phosphate (Pi). The degree of PCr change  during exercise was calculated as PCr loss = standardized PCrrest − standardized PCrlowest.Before the study, the 1-RM of plantar-flexion exercise, i.e., the maximal weight of exercise that can be done only once, was determined with the participant in the supine position as described1H-MRS on a 1.5-T whole-body scanner system  as described28.We measured the IMCL content in the resting tibialis anterior muscle at the level of the muscle belly of the calf using t-test for continuous variables and the χ2 test for categorical variables to compare the data between the CHF and control groups. We examined correlations by performing a linear regression analysis using Pearson's correlation coefficient. Statistical analyses were performed using GraphPad Prism ver. 8 , and significance was defined as p < 0.05.Data are expressed as the mean ± standard deviation (SD) or n (%). We used Student's


The long-term clinical and physiological consequences of COVID-19 infection remain unclear. While fatigue has emerged as a common symptom following infection, little is known about its links with autonomic dysfunction. SARS-CoV-2 is known to infect endothelial cells in acute infection, resulting in autonomic dysfunction. Here we set out to test the hypothesis that this results in persistent autonomic dysfunction and is associated with post-COVID fatigue in convalescent patients.We recruited 20 fatigued and 20 non-fatigued post-COVID patients  female, median time to follow up 166.5 days). Fatigue was assessed using the Chalder Fatigue Scale. These underwent the Ewing’s autonomic function test battery, including deep breathing, active standing, Valsalva manoeuvre and cold-pressor testing, with continuous electrocardiogram and blood pressure monitoring, as well as near-infrared spectroscopy-based cerebral oxygenation. 24-hour ambulatory blood pressure monitoring was also conducted, and patients completed the generalised anxiety disorder-7 questionnaire. We assessed between-group differences in autonomic function test results and used unadjusted and adjusted linear regression to investigate the relationship between fatigue, anxiety, and autonomic test results.We found no pathological differences between fatigued and non-fatigued patients on autonomic testing or on 24-hour blood pressure monitoring. Symptoms of orthostatic intolerance were reported by 70% of the fatigued cohort at the time of active standing, with no associated physiological abnormality detected. Fatigue was strongly associated with increased anxiety (p <0.001), with no patients having a pre-existing diagnosis of anxiety.These results demonstrate the significant burden of fatigue, symptoms of autonomic dysfunction and anxiety in the aftermath of COVID-19 infection, but reassuringly do not demonstrate pathological findings on autonomic testing. Similarng COVID . The pring COVID ,8.Autonomic dysfunction most commonly manifests within the cardiovascular system with tachycardia, hypotension and vasovagal syncope . It has We set out to investigate the presence of autonomic dysfunction following SARS-CoV-2 infection and its relationship with post-COVID fatigue.This study was carried out in the falls and syncope unit at St James’s Hospital, Dublin, Ireland. Patients were recruited via the post-COVID-19 clinic at the same hospital between August and October 2020. The inclusion criteria were positive SARS-CoV-2 RT-PCR test at time of acute illness and patients aged >18 years of age. Patients were excluded if they were in receipt of any medication that directly affected heart rate or blood pressure, such as beta blockers and anti-hypertensives, or were unable to complete any part of the assessment. Demographic data was recorded, and severity of initial infection was graded based on requirement for hospitalisation. Proportions of healthcare workers were matched between fatigued and non-fatigued cohorts. The population selected was representative of the population seen in our outpatient clinic and those reported from elsewhere . EthicalBetter than usual = 0, No worse than usual = 1, worse than usual = 2, much worse than usual = 3). From this a global score was constructed out of a total of 33, with a score of 11 indicating no difference from prior to infection, reflecting answers of no worse than usual [Better than usual/No worse than usual) are scored a zero and scores 2 and 3  are scored a 1. A total of four or higher meets the case definition of fatigue [Fatigue was assessed using the Chalder Fatigue Scale (CFQ-11) at time of outpatient appointment and at time of autonomic testing ,23. Partan usual . We also fatigue –27.The generalised anxiety disorder-7 (GAD7) questionnaire was also completed by all patients. This is a well-validated screening tool and symptom severity measure for the four most common anxiety disorders –30.™ and brachial calibration was applied during patient setup.Ewing’s autonomic function test battery was performed, comprising of deep breathing, active stand, Valsalva manoeuvre, and cold pressor testing . A 12-leConcurrent continuous cerebral oxygenation measures using near-infrared spectroscopy (NIRs) was also recorded  throughout to derive a tissue oxygenation/saturation index (TSI). A NIRs sensor was placed on the left side of the forehead to measure frontal lobe cerebral oxygenation, centred at 3cm lateral and 3.5cm above the nasion with an opaque head bandage applied to provide environmental light protection.While lying supine, the patient was instructed to take controlled deep breaths in and out at a rate of 6 breaths per minute. Following two minutes of sitting, patients then rested in the supine position for ten minutes. This period was used to derive measures of HRV. Patients were then asked to stand as quickly as possible under the supervision of a researcher and continued to stand for five minutes. During this period, they were asked to report any symptoms of light-headedness, dizziness, palpitations or chest discomfort. Subsequently, the patient was seated in a chair for two minutes. They were then instructed to perform a Valsalva manoeuvre by forced expiration against a disposable air flow restrictor and directed to maintain an expiratory pressure of 40mmHg for a minimum of 8 seconds, recording phase I  to phase IV . This procedure was repeated twice. Finally, the patient was asked to place their hand in a basin of iced water until the diastolic BP rose from baseline by 10mmHg or for one minute, whichever occurred earliest.th beat/15th beat ratio), R-R interval, and the Valsalva ratio (R-R post / R-R during). The blood pressure response to active stand, Valsalva and cold pressor testing was also recorded and analysed using proprietary software (Novascope V 1.10) and custom-written software in MATLAB R2017a  as described elsewhere [The following data were extracted by a bioengineer blinded to the patient diagnosis: heart rate responses to deep breathing (expiratory/inspiratory ratio), active stand heart rate ratio (30lsewhere . Furtherlsewhere . Blood plsewhere –37. TherA 24-hour ambulatory blood pressure monitor (24H ABPM) was recorded for each patient. This allowed extraction of mean and standard deviation of systolic BP, diastolic BP, mean arterial pressure (MAP), pulse pressure (PP) and heart rate (HR) over 24 hours, as well as mean values for day and night-time.t), Wilcoxon rank-sum (z) and Chi-squared test (χ2) as appropriate following Shapiro-Wilk testing for normality. Linear regression, with CFQ-11 score as the dependent variable, was used to investigate the relationship with autonomic function testing results under both unadjusted and adjusted  conditions. Results are reported as β coefficients and confidence intervals (CIs) with associated p-values. Bonferroni correction was applied to correct for multiple testing.All statistical analysis was carried out using STATA v15.0  and statistical significance considered p <0.05. Descriptive statistics are reported as means with standard deviations (SD) and medians with interquartile ranges (IQR) as appropriate. Univariate analysis was performed on important demographic variables and autonomic test results to examine differences between fatigued and non-fatigued individuals, using t-test , while the median time to follow up was 166.5 days (IQR 154.5–179). There were no differences in demographics, body mass index, medical history or clinical frailty status between the cohorts . No patiAll patients underwent autonomic testing as per protocol. There were no differences in the heart rate response to deep breathing  or time Following active standing, 14/20 (70%) of the patients in the fatigued cohort reported at least one of the following symptoms: palpitations, dizziness, feeling lightheaded, or chest discomfort. No patients in the non-fatigued cohort reported any symptoms during active standing. There were no significant differences in HR, systolic BP or diastolic BP between fatigued and non-fatigued individuals at any timepoint during the active stand . FurtherCerebral blood flow was also assessed during active standing. There were no significant differences between groups in changes from baseline TSI to nadir TSI within 30 seconds of standing, TSI overshoot, or nadir TSI at any point during active standing . The meaz -3.14, p 0.002).All participants completed the GAD7 questionnaire to assess anxiety. Significantly higher levels of anxiety were noted in patients that met the case definition of fatigue versus those that did not (median anxiety score non-fatigued 0 (IQR 0–6) versus fatigued 5.5 (3.5–10.5), We next assessed the relationship between total fatigue scores and both autonomic test results and anxiety, as this provides a more granular assessment than a binary fatigue case definition. Following unadjusted and adjusted linear regression, significant associations persisted between total fatigue score and both blood pressure response to Valsalva and anxiety score .Finally, differences in heart rate variability and blood pressure variability between fatigued and non-fatigued cases were assessed over 24 hours. There were no significant differences between systolic blood pressure, diastolic blood pressure, or heart rate between groups either over the 24-hour monitored period or when divided into day- and night-time measurements. Similarly, there were no differences in MAP between the groups .We present comprehensive autonomic assessment of patients with post-COVID fatigue and contextualise the results with matched non-fatigued COVID survivors at a median of 166 days following infection. We find no objective findings of autonomic dysfunction, with no significant pathological differences noted between groups in any of the Ewing’s battery parameters. We report a strong association with post-COVID fatigue and anxiety. This is notable, given that none of the participants had an antecedent diagnosis of anxiety. We also demonstrate a significant symptom burden, with 70% of fatigued patients reporting symptoms at time of the active stand, but these were independent of neurocardiovascular changes. Finally, we demonstrate the impact of post-COVID fatigue on daily function, with 35% of our fatigued cohort not yet returned to full-time employment.Given that COVID-19 is a novel infection, studies of cardiovascular and autonomic dysfunction following infection are limited. Thus, it is reassuring that we do not seen any evidence of persistent autonomic dysfunction following COVID-19, particularly given that endothelial cells are affected during acute COVID-19 infection. Prior studies in the area of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) have shown a variety of changes in autonomic function. Symptoms of autonomic dysfunction have been shown in subsets of CFS patients . HoweverThe significant difference in blood pressure response to the Valsalva manoeuvre in phase IV is noteworthy. While both non-fatigued and fatigued patients have responses that are within normal physiological limits, the response is more marked in those without fatigue. Discrepancies in expiratory effort can lead to this occurring . Volume long COVID, namely young females [The discrepancies in our study with previous findings in the area of CFS and ME suggest that post-COVID fatigue is distinct from these conditions, despite sharing similar clinical characteristics. Similarly, we did not see changes that would fit with a diagnosis of POTS. The robust physiological assessments performed in our study clearly demonstrate the absence of significant dysautonomia in post-COVID fatigue. Furthermore, our population is representative of those reported to be most at-risk from developing  females ,46,47. TWe do however see a strong association between post-COVID-19 fatigue and anxiety. This is of particular note, given that none of the patients in this study had a pre-existing diagnosis of anxiety, nor were they taking any anxiolytic medications. The association between chronic fatigue and anxiety is well-described ,49. The Our study has some limitations of note. Our sample cohort is not large enough to investigate associations with each individual symptom reported, and these are grouped together. However, our cohorts are well-matched, and this is evident by the limited effect multiple linear regression has on the associations investigated. We did not measure serological markers of the adrenergic system. Ewing’s battery is however a robust non-invasive measure of this system. The GAD7 is a rapid screening tool, and more detailed anxiety assessments are warranted in future studies. Furthermore, our cohort has a large proportion of healthcare workers, and anxiety may be due to occupational stress during the pandemic. Finally, we did not investigate alternative causes of symptoms that mimic autonomic dysfunction, such as vestibular dysfunction. We would suggest that this is an area worthy of further study.Our study demonstrates the significant burden of fatigue at a median interval of 166 days following COVID-19 infection, with significant associated anxiety as well as failure to return to employment. We demonstrate symptoms of autonomic dysfunction at active standing without a physiological cardiovascular cause. These findings suggest that autonomic dysfunction is not a significant contributor to post-COVID-19 fatigue.S1 TableT-test and Wilcoxon rank-sum tests used to assess between-group differences. ms = milliseconds; SD = standard deviation. IQR = interquartile range.(DOCX)Click here for additional data file.S2 TableChanges in heart rate, blood pressure and cerebral oxygenation during active stand, as well as heart rate variability prior to active stand. T-test and Wilcoxon rank-sum used to assess between-group differences. HR = heart rate, SBP = systolic blood pressure, DBP = diastolic blood pressure. Δ = change from baseline measurement. Δ1020 = change from 10 seconds to 20 seconds. IQR = interquartile range. SD = standard deviation. TSI = tissue saturation index.(DOCX)Click here for additional data file.


Hypotension is a common occurrence, especially in anesthetized patients and in critical patients suffering from hypovolemia due to shock and sepsis. Hypotension can also occur in normovolemic animals, anesthetized or conscious, under conditions of vasodilation or decreased cardiac function. The main consequence of hypotension is decreased organ perfusion and tissue injury/dysfunction. In the human literature there is no consensus on what is the threshold value for hypotension, and ranges from < 80 to < 100 mmHg for systolic blood pressure and from < 50 to < 70 mmHg for mean arterial blood pressure have been referenced for intraoperative hypotension. In veterinary medicine, similar values are referenced, despite marked differences in normal arterial blood pressure between species and with respect to humans. Therapeutic intervention involves fluid therapy to normalize volemia and use of sympathomimetics to enhance cardiac function and regulate peripheral vascular resistance. Despite these therapeutic measures, there is a subset of patients that are seemingly refractory and exhibit persistent hypotension. This review covers the physiological aspects that govern arterial blood pressure control and blood flow to tissues/organs, the pathophysiological mechanisms involved in hypotension and refractory hypotension, and therapeutic considerations and expectations that include proper interpretation of cardiovascular parameters, fluid recommendations and therapy rates, use of sympathomimetics and vasopressors, and newer approaches derived from the human literature. In simple terms, hypotension is a lower than normal arterial blood pressure. However, this definition does not imply when and at what specific values is hypotension harmful to the patient. Hypotension is a common occurrence, especially in anesthetized animals and in critical patients suffering from hypovolemia due to shock and sepsis.Mean arterial blood pressure values of 60 mmHg or less and systolic arterial blood pressure values of 80 mmHg or less have been reported as indicative of excessive hypotension in animals, and ideally these pressures should be maintain above 80 mmHg and 100 mmHg for mean and systolic arterial blood pressure, respectively , so the In humans, where studies have been completed with sufficient statistical power, there is still no consensus on what is the threshold value for hypotension to provide a widely accepted definition –18 and tThe major function of the nervous system on the circulatory system is to control arterial blood pressure by allowing adequate and independent blood flow to the individual needs of tissues and organs, and regardless of the amount of blood that flows to any given tissue, arterial blood pressure remains constant .Arterial blood pressure control is necessary for short- and long-term situations, and it differs between. Short-term refers to acute changes , whereas long-term refers to chronic changes (hours to weeks). Short-term control occurs through changes that affect both cardiac output and arterial blood pressure, and include variations in vascular resistance and compliance, contractility, heart rate and blood volume  20). An. An20). Individually, each of these factors result in specific changes in arterial blood pressure and/or cardiac output; however, with an intact nervous system it is the interaction between factors that determines the final cardiovascular effect. In simple terms, Ohm's Law  can be used to define the interaction between arterial blood pressure and cardiac output, where I is equivalent to cardiac output (CO), V is arterial blood pressure (ABP), and R is vascular resistance (VR), so that CO = ABP ÷ VR. For example, vascular resistance on its own can affect arterial blood pressure and cardiac output in opposite ways, a decrease in vascular resistance lowers arterial blood pressure and could increase cardiac output, whereas an increase in vascular resistance results in higher arterial blood pressure and limits cardiac output .Volume administration increases cardiac output by increasing preload, and can potentially increase arterial blood pressure if the nervous system does not exert a reflex control over vascular resistance. This effect of volume administration without a change in arterial blood pressure is notable in conditions of normovolemia, where an increase in circulating volume results in a decrease in vascular resistance , 22, 23 An increase in heart rate can result in an increase in cardiac output and arterial blood pressure, but only if the circulating volume is ideal. A low circulating volume (hypovolemia) results in low venous return (preload) and a low right atrial pressure, even below 0 mmHg. The veins entering the chest will collapse with subatmospheric pressures and without proper preload the cardiac output and arterial blood pressure do not benefit from an increase in heart rate . ConversLong-term control of cardiac output and arterial blood pressure is the result of adaptation of baroreceptors within hours to days to changes in circulating volume and arterial blood pressure, of the instauration of higher vascular resistance that results in higher arterial blood pressure and minimal changes in cardiac output, and of an active participation of the kidney that responds to the increase in arterial blood pressure with endocrine and electrolyte mechanisms to control pressure and volume by increasing urinary output .Hypotension has been associated with decreased organ perfusion and injury/dysfunction, which in humans may include myocardial infarction , 30, 31,In general, most studies in humans have associated mean arterial blood pressures of ≤ 55 mmHg with adverse cardiac- and renal-related outcomes, and the duration of the hypotensive episode increases the risk of that adverse outcome , 31, 34.Several aspects need to be considered to interpret hypotension. First of all, the threshold value for hypotension should not be generalized between conscious and anesthetized patients, since as stated before, values differed in the two situations and values also differ between species. A patient positioned in recumbency  position, as it happens during anesthesia, offers the heart ideal work conditions because the effect of gravity is reduced by leveling all organs and tissues with the heart, and therefore changes to increase vascular resistance become less necessary in stable patients. In the standing position, gravitational forces result in lower pressures in the upper part of the body and higher pressures in the lower part of the body, which is counteracted by an increase in arterial vascular resistance and pulse rate, so that mean arterial blood pressure remains constant or slightly elevated throughout the body . In addiIt is also difficult to conclude when hypotension is significant enough to result in an adverse outcome, which is further confounded by how hypotension is defined in any study. Findings from different studies cannot be generalized because small changes in the selected threshold values for hypotension among human studies can result in wide differences in the incidence of intraoperative hypotension (5–99%) and do not necessarily reflect organ dysfunction as a consequence of hypotension . More imStudies in healthy dogs and foals under research conditions, where hypotension was induced by deep anesthesia with inhalant anesthetics in normovolemic conditions, resulted in no adverse outcomes despite mean arterial blood pressures of 24 mmHg for at least 15 min in foals  and 46 mHypotension that persists, despite appropriate therapeutic measures that consistently correct it, probably exhibit refractory hypotension. Refractory hypotension is most commonly encountered under conditions of shock due to hypovolemia or sepsis, but can also include cardiogenic, neurogenic, and anaphylactic shock . RefractHypovolemic (hemorrhagic) shock is due to a reduced intravascular volume (preload), which results in low cardiac output and arterial blood pressure. In human medicine hypovolemic shock is rated into four classes, from least to most critical, according to the “Advanced Trauma Life Support (ATLS®)” guidelines of the American College of Surgeons. The patient is allocated to one of the classes according to degree of blood loss  and degree of alteration of vital signs, including pulse rate, blood pressure, pulse pressure, respiratory rate, mental status, and urinary output . HoweverIn conscious, splenectomized research dogs, removal of 43 mL/kg of blood  in 10 mThe response to blood loss is different under conditions of general anesthesia, both with inhalant and injectable anesthetics, because these drugs inhibit, in a dose-dependent fashion, baroreceptor reflex and sympathetic activity, which interferes with normal short-term control –49. In aSeptic shock is discussed in depth in the chapter “Fluid Therapy in Dogs and Cats with Sepsis.” In brief, septic shock is a type of distributive shock, in which infection results in organ dysfunction due to a dysregulated response from the patient that results in injury to its own tissues and organs . PatientAccording to the latest consensus for sepsis and septic shock in humans (Sepsis 3.0), patients clinically exhibit persistent hypotension that requires of vasopressors to maintain a mean arterial blood pressure ≥ 65 mmHg and a serum lactate level > 2 mmol/L, despite adequate volume resuscitation and the absence of hypovolemia . In addiThe vasodilation that results from sepsis is the result of several factors that enhance vasodilatory- and inhibit vasoconstrictor mechanisms. These include an unregulated synthesis of nitric oxide, a potent vasodilator, in response to cytokines released during septic and hemorrhagic shock. In dogs with septic peritonitis, levels of the inflammatory cytokines C-C motif chemokine ligand 2 (CCL2) and interleukin 6 (IL-6) were significantly higher than in non-septic dogs , which cAnother mechanism is the result of conditions of local acidosis, with hydrogen ions and lactic acid production from anaerobic metabolism , 68, 69.2+, preventing vasoconstriction and resulting in vasodilation (The prostaglandin prostacyclin is found in increased concentrations in conditions of septic shock . Prostacdilation .1a) present in vascular smooth muscle and helps with short-term control of arterial blood pressure under conditions of hemorrhage or sepsis, but this process requires of high circulating concentrations of vasopressin that depletes the stores within 1-h under conditions of profound baroreflex stimulation . These include two main reasons, hypovolemia and/or sepsis, and within them the whole spectrum of possibilities, from blood loss, dehydration, sympathetic inactivity or inability to respond, metabolic acidosis, and endotoxemia. Sepsis however, is the most common cause of refractory hypotension due to the vasodilatory effects that result from it , 43, 54.Monitoring of cardiovascular function to assess the condition of the patient and response to treatment is primordial. Arterial blood pressure is readily monitored by non-invasive methods; unfortunately they are inaccurate and unreliable in hypotensive patients . Direct This review starts with vasopressors as the first line of therapy since the basic pathology is the decrease in vascular resistance. However, a combination of at least vasopressors and fluids should be instituted simultaneously for better success in improving arterial blood pressure. The most recent guidelines for management of sepsis and septic shock in people, from 2016, recommends an initial target mean arterial pressure of 65 mmHg in patients with septic shock requiring vasopressors .1a receptor action.Vasopressor therapy aims at improving tissue perfusion through vasoconstriction and improved contractility. Norepinephrine, dopamine, epinephrine and phenylephrine are catecholamines used for their vasoconstrictor actions through the alpha-1 receptor, and inotropic actions through the beta-1 receptor, except for phenylephrine that lacks the latter. Arginine vasopressin (vasopressin) is also used for its vasoconstrictor effects, through its V1a receptor are linked to G-protein-coupled receptors that result in smooth muscle contraction. Attachment of these agonists to the respective receptors triggers the stimulation of phospholipase C, which generates the production of inositol triphosphate (IP3) and diacylglycerol (DAG). These two substances interact between them to promote smooth muscle contraction; IP3 diffuses into the cell to act on an IP3-sensitive Ca2+ channel on the surface of the endoplasmic reticulum, facilitating the release of Ca2+ into the cytoplasm, which stimulates the calmodulin (CM) pathway by forming a Ca2+-CM complex that activates the myosin light-chain kinase and with the presence of ATP, it phosphorylates the myosin light chain and causes vasoconstriction  pathway, responsible for activating rho kinase, which prevents smooth muscle relaxation from occurring by inhibiting the myosin light chain phosphatase, as well as helps release reactive oxygen species, which are useful in increasing the sensitivity to Ca2+ and leads to additional stimulation of rho kinase , cardiac troponin I (cTnI) and myosin binding protein (MyBP-C) , which activates L-type Ca(MyBP-C) , 75. Phorylation .Patients with refractory hypotension under general anesthesia should be supported for contractility through beta-adrenergic inotropic effects because of the vasodilation from inhalant anesthetics and their negative dose-dependent effects on contractility , 53. IdeThe guidelines for management of sepsis and septic shock have published recommendations on the different types of vasopressors that should be used for resuscitation upon reviewing the literature; the higher the quality of evidence, the more likely a strong recommendation is issued . AccordiVasopressin has been considered the second line-drug due to its catecholamine-sparing properties , 54. The1a receptor does not result in arrhythmias and can increase systemic arterial blood pressure even in the presence of acidemia  and crystalloids , 87, 88.The guidelines for management of sepsis and septic shock in people recommends fluids as follows: a strong recommendation/moderate quality of evidence for crystalloids; a weak recommendation/low quality evidence for use of either balanced crystalloids or saline; a weak recommendation/low quality of evidence for albumin in addition to crystalloids; a strong recommendation/high quality of evidence against hydroxyethyl starches; and a weak recommendation/low quality of evidence for crystalloids over gelatins .Studies in normovolemic and normotensive dogs, maintained at useful clinical inhalant anesthetic concentrations to allow surgery 1.1–1.25 MAC), arterial blood pressure values and the effects on packed cell volume and total protein were similar in groups receiving no fluid therapy or up to 20 mL/kg/h of isotonic crystalloids , 25, bec MAC, artIn hypotensive models using healthy research dogs that were normovolemic and maintained at a systolic arterial blood pressure of 80 mmHg with a deep level of isoflurane anesthesia [3.1–3.4% end-tidal (2.4–2.8 MAC)], isotonic crystalloids, at fast and high volume infusion rates used for shock of 80 mL/kg for up to 1-h did not improve blood pressure, whereas the colloid hetastarch administered at a rate of 80 mL/kg/h to maximum volume 40 mL/kg, restored systolic pressures to within 10% of baseline values predetermined at 1.6–1.7% (1.3 MAC) in 66% of cases . In a six VR), arterial blood pressure was maintained as a result of an improvement in cardiac output from the expansion in blood and plasma volume (x SV), an increase in myocardial contractility is likely responsible for the improvement in cardiac output, as a result of the expanded circulating volume that decreases viscosity from hemodilution of the packed cell volume and total protein, which in association with the lower vascular resistance facilitates the work of the heart, even if arterial blood pressure does not change  .In patients receiving corticosteroid therapy for chronic autoimmune or inflammatory diseases and in patients receiving replacement therapy because of chronic primary or secondary adrenal insufficiency, it is important that they continue receiving their current dose of corticosteroids to maintain cardiovascular function, especially if general anesthesia is planned. If the patient exhibits refractory hypotension, supplemental hydrocortisone therapy should be considered.3 and DAG and stimulation of the JAK2 pathway (Angiotensin II has been recommended due to its actions on the AT1 receptor, a G-protein-coupled receptor, and stimulates the same transduction pathways as vasopressors through activation of phospholipase C for the generation of IP pathway , all of  pathway .Angiotensin II was evaluated in a double blind, randomized, controlled trial in patients with vasodilatory shock that were not responsive to high doses of vasopressors . In thisAngiotensin II is not mentioned in the most current guidelines for management of sepsis and septic shock  because In vitro, methylene blue also suppresses the production and release of prostacyclin, in both the presence and absence of pro-inflammatory cytokines, in dog renal artery smooth muscle cells, which may also contribute to prevent vasodilation by inhibiting the formation of c-AMP, which normally would prevent cytoplasmic Ca2+ from causing vasoconstriction (Methylene blue inhibits nitric oxide synthase, preventing the production of nitric oxide and cGMP, therefore vasodilation does not occur . In vitrtriction .Methylene blue has been used successfully at decreasing mortality in vasodilatory shock after cardiopulmonary bypass at IV doses of 1–2 mg/kg to counteract refractory hypotension that requires of high inotropic support . HoweverSedation is often required in human septic patients. Dexmedetomidine has been used for this purpose and spiked interest due to its central and peripheral actions on sympathetic activity and vascular tone. Dexmedetomidine causes vasoconstriction and an increase in mean arterial pressure through its post-synaptic alpha-1 and−2 adrenergic actions, but it can be used also as an antihypertensive drug due to its presynaptic alpha-2 actions that induce a negative feedback on norepinephrine secretion, which causes hypotension . HoweverIn human patients with septic shock and initially maintained sedated with propofol and remifentanil, while receiving norepinephrine to maintain adequate mean arterial blood pressures, had higher norepinephrine requirements than when dexmedetomidine was used to replace the propofol, and norepinephrine requirements increased again when sedation was switched back to propofol .The use of dexmedetomidine is not mentioned in the current guidelines for management of sepsis and septic shock .In summary, refractory hypotension should be addressed aggressively to reestablish arterial blood pressure control and blood flow to tissues/organs. Therapeutic actions include fluid therapy with the use of sympathomimetics and vasopressors that help overcome or at least minimize the ongoing state of vasoplegia, In anesthetized patients, the vasodilatory effects of inhalant anesthetics contribute to the hypotension and anesthesia time should be reduced if at all possible, as well as consider the use of balanced techniques that could help avoid excessive inhibition of sympathetic activity.AV: manuscript writing.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The association between accessory renal artery (ARA) and hypertension remains not fully understood. We observed the association between ARA and clinical characteristics among middle-aged patients with primary hypertension. n = 108) and ARA (n = 54) group. Direct renin concentration (DRC), plasma aldosterone concentration (PAC), ABPM, echocardiography, creatinine, and glomerular filtration rate were compared between the two groups.  One hundred and sixty-two middle-aged  patients with primary hypertension were enrolled, and patients underwent Computed Tomography Angiography (CTA) of renal arteries, ambulatory blood pressure monitor (ABPM), echocardiography, physical examination, and routine blood chemistry examinations. According to the CTA results, patients were divided into a non-ARA (P=0.002) was significantly higher in the ARA group than in the non-ARA group. However, PAC (ng/dL)  vs. 116.50 , P=0.103) was similar between these two groups. ABPM (mmHg) results showed that daytime , night time , and 24 h blood pressure  were significantly higher in the ARA group than in the non-ARA group. Accordingly, echocardiographic-derived posterior left ventricular wall thickness value was higher in the ARA group than in the non-ARA group.  DRC (mU/L)  vs. 18.24 ,  ARA is related to higher blood pressure and higher direct renin concentration in middle-aged patients with primary hypertension, and these patients deserve stricter blood pressure control. Our results provide important evidence for that ARA is a cause of hypertension and target organs damages. Hypertension is one of the major risk factors for various cardiovascular events, such as stroke, myocardial infarction, heart failure, and chronic kidney disease –3. UnforThere are about 22–24% hypertensive patients having accessory renal arteries (ARAs) , 8. ARAsIn the present study, we observed the association between ARA and clinical characteristics among middle-aged patients with primary hypertension who underwent complete pharmacological wash-out to elimination the influence of the medicines on the sympathetic nerve system and renin-angiotensin system.β-blockers, dihydropyridine calcium blockers, and clonidine were withdrawn for at least 2 weeks; aldosterone receptor antagonists were withdrawn for at least 6 weeks; diuretic was withdrawn for at least 4 weeks. Patients were prescribed nondihydropyridine calcium blocker (diltiazem) and/or α-blockers (doxazosine and terazosin) to control blood pressure. According to the CTA results, the patients were divided into a non-ARA group (n = 108) and ARA group (n = 54), and the clinical characteristics of them were collected and summarized in Between June 2017 and January 2019, 162 patients with primary hypertension undergoing Computed Tomography Angiography (CTA) of renal arteries were enrolled in this study. All the patients were between 18 and 65 years of age and underwent adequately preparation before performing CTA, echocardiography, ambulatory blood pressure monitor (ABPM), physical examination, and routine blood chemistry examinations. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, t-Test. Continuous variables with nonnormal distribution were expressed as median (25th to 75th percentile) and compared by the nonparametric U test. Categorical variables were expressed as percentage and compared by the chi-square test. P < 0.05 was defined to be statistically significant.Data were analyzed by using the SPSS software . The Kolmogorov–Smirnov test was used to determine whether the data were normally distributed. Continuous variables with normal distribution were expressed as mean ± SD and compared by the Independent-Sample There were 162 patients with primary hypertension were enrolled in this study. According to the CTA results, there were 108 patients without ARA and 54 patients with ARA. The baseline characteristics of them showed no significant differences .Firstly, we estimated DRC and plasma aldosterone concentration (PAC) of these patients. DRC was significantly increased in the ARA group compared with that of the non-ARA group . UnexpecSecondly, we examined whether there was difference in the level of blood pressure between these patients. The results of ABPM showed that both SBP (systolic blood pressure) and DBP (diastolic blood pressure) in day/night/24 h in the ARA group were higher than those of the non-ARA group . These rThen, we assessed whether patients with ARA had severe target organs damages. Although interventricular septal thickness was mildly increased, there was a significant increase in left ventricular posterior wall thickness in the ARA group as measured by echocardiography . It suggTo investigate whether ARA was associated with hypertension accurately, middle-aged patients with primary hypertension without renal artery stenosis were enrolled in the present study. In addition, compared with previous study, patients in our study underwent complete pharmacological wash-out to elimination the influence of the medicines on the sympathetic nerve system and renin-angiotensin system. Therefore, the results of the present study provided stronger evidences for the relationship between ARA and clinical characteristics among middle-aged patients with primary hypertension.The relationship between ARA and pathogenesis of hypertension was firstly suggested by the observational study conducted by Kuczera et al. in 2009 . ARA is We recognize some potential limitations in our study. This is a single-center study with a small sample size of middle-aged patients with primary hypertension. Multicenter research with adequate sample size, consisting of hypertensive patients and normotensive population, is essential to acquire more accurate relationship between ARA and hypertension. Besides, the volume of blood flow in ARA and blood flow perfusion of kidney is not estimated in this study. Mechanical investigations are also important to uncover the role of ARA in elevated blood pressure in the future.In conclusion, we confirmed that ARA contributed to higher blood pressure in patients with primary hypertension through excessive renin and activation of the renin-angiotensin system. In addition, we verified that patients with ARA had severe target organs damages. Therefore, these patients deserved stricter blood pressure control to prevent of severe cardiovascular events. Our results provided significant evidences for the aggressive treatment of hypertensive patients with ARA in daily clinical practice.


Secondary hyperparathyroidism (SHPTH) is a major complication in patients on maintenance hemodialysis burdened with high cardiovascular risk. Hypertension is also a high prevalence complication contributing to an increase in the mortality rate in hemodialysis patients. A possible association between SHPTH and hypertension has been widely reported in the literature and several pathogenetic mechanisms have been described. There is evidence that the decrease of plasma iPTH levels are correlated with hypertension correction in hemodialysis patients undergoing parathyroidectomy and oral calcimimetics administration. We have observed a similar behaviour also in a patient on chronic hemodialysis treated with Etelcalcetide. Even if this is an isolated observation, it could stimulate future investigation, possibly in dedicated clinical trials. Secondary hyperparathyroidism (SHPTH) is a universal complication of chronic kidney disease (CKD) affecting more than 80% of hemodialysis patients ,2. This Hypertension is another relevant and highly prevalent cardiovascular risk factor in hemodialysis patients, as widely reported in the literature ,12,13,14Despite the association of SHPTH and hypertension being very frequent in hemodialysis patients with a possible exponential increase of cardiovascular risk , these tThis literature analysis is aimed to provide an updated overview of what is known on the pathophysiological basis of the SHPTH and hypertension association. Moreover, a discussion on novel therapeutic approaches to SHPTH and their impact on blood pressure will include our experience on a single clinical case of blood pressure normalization in a hemodialysis patient with SHPTH treated with Etelcalcetide.+-Cl− transporter expression in convoluted distal tubule is at the basis of a sodium-retentive hypertensive mechanism [The suspicion for the existence of a pathophysiological relationship between hyperparathyroidism and blood pressure increase has far-away origins. In 1996, Goldsmith et al. published the results of a study conducted on 21 hypertensive hemodialysis patients with tertiary hyperparathyroidism that had undergone parathyroidectomy (PTX) . Interesechanism .As for several reports, structural and hemodynamic pathologic changes associated to SHPTH appear to be partially reversible, since an improvement of arterial stiffness and survival has been observed after PTX in patients that also achieved normal serum calcium levels ,27. NumeAs described in the previous paragraph, data on the beneficial effects of PTX on BP control in hemodialysis patients are limited, but undoubtedly current evidence highlight an association between hyperparathyroidism and hypertension. Little is known, however, about the effect of secondary hyperparathyroidism therapy on BP.Besides the indisputable role of phosphate chelating agents, vitamin analogues in the control of iPTH secretion, the advent of calcimimetic agents has profoundly changed and improved the therapeutic approach to SHPTH.Cinacalcet has been the first available calcimimetic agent . The EVOEtelcalcetide is a novel intravenous calcimimetic agent approved by the FDA in 2017 for the treatment of SHPTH in adult patients with chronic kidney disease (CKD) on hemodialysis.This approval was largely based on positive results from two randomized, double-blind, placebo-controlled Phase 3 studies . An aggrIn both studies, the primary end-point was achieved in a significantly higher percentage of patients in the Etelcalcetide group compared to controls. Similarly, a greater proportion of patients within the treatment group compared to the placebo, reached the secondary end-points during the EAP.In a pooled analysis of the two Phase 3 placebo-controlled studies, as expected, asymptomatic and symptomatic hypocalcemia occurred more frequently in patients treated with Etelcalcetide compared to placebo. Other commonly reported adverse reactions were muscle spasms, diarrhea, nausea, vomiting, headache, and paresthesia/hypoesthesia. The impact of Etelcalcetide on blood pressure was instead not explored.In the first trial exploring the impact of Etelcalcetide vs. Cinacalcet on iPTH, Etelcalcetide resulted more efficacious in lowering iPTH, but also, in this case, no significant differences were reported relating to blood pressure. However, mean baseline BP in both studied groups was normal and indeed, this did not stimulate a secondary analysis. However, it is noticeable that in the Etelcalcetide group, a higher percentage of patients (6.8%) than in the Cinacalcet group (2.9%) showed hypotension within common side adverse effects. Even the number of hypocalcemia episodes was higher in the Etelcalcetide group . As detaWe recently experienced the effect of Etelcalcetide on blood pressure in a 37 years old young male patient on chronic hemodialysis in the past three years. This patient was complicated with SHPTH in treatment with Cinacalcet 30 mg/die  and had baseline iPTH 421 pg/mL. At the time, his home therapy also included Lanthanum carbonate 1 g twice/day, Irbesartan 150 mg/day and Omeprazole 20 mg/day. So far, blood pressure was well controlled and stable during hemodialysis sessions. In January 2018, a sudden increase in intradialytic blood pressure and heart rate (mean systolic blood pressure was 190/110 mmHg and mean heart rate was 110 bpm) was accompanied by a significant increase in iPTH, . An electrocardiogram and an echocardiogram were performed at that time, not showing any noteworthy change except for a sinusal tachicardia and previously known ventricular hypertrophy. The uncontrolled hypertension was resistant to both pharmacological therapy increase  and dry weight reduction according to bioimpedentiometry results . Anti-RAA possible association between SHPTH and hypertension in hemodialysis patients has been widely reported in the literature and several pathogenetic mechanisms have also been disclosed ,18,19,20