Osteoporotic fracture associated with calcium dysregulation is more common in patients with kidney stones. However, little is known about the association of kidney stones and bone health status in patients with chronic kidney disease (CKD). This retrospective medical record-based study included 2282 patients with stable stage 3–4 CKD between 2007 and 2017. Of these, 113 patients were diagnosed with kidney stones. Propensity score matching for 226 patients with and without kidney stones showed that osteoporotic fracture occurred more often in patients with kidney stones  than in patients without kidney stones , resulting in rates of 5.56 and 2.63/100 patient-years, respectively (p < 0.01). In particular, Cox proportional hazard analysis revealed that kidney stones were significantly associated with osteoporotic fracture, even after adjusting for age, sex, body mass index, kidney stones, estimated glomerular filtration rate, excessive alcohol consumption, current smoking, and steroid use in patients with CKD stage 3–4 . This study showed that the presence of kidney stones was a significant predictor for osteoporotic fracture in patients with CKD, suggesting that it should be considered as a clinical risk factor for osteoporotic fracture in them. Generally, CKD patients have a higher osteoporotic fracture risk compared with the general population2. Bone changes in patients with CKD are characterized by abnormalities of bone turnover, mineralization, volume, linear growth, and strength3. Therefore, it is important to predict osteoporotic fracture risk in these patients. Although revised Kidney Disease Improving Global Outcomes guidelines recommend bone mineral density (BMD) measurement with dual-energy X-ray absorptiometry (DXA) to assess osteoporotic fracture risk in these patients4, the ability to predict fracture risk remains limited. Bone strength is determined by both the density and quality of bone. However, DXA BMD only measures the density of bone by assessing the amount of bone mineral. To overcome this limitation, high-resolution peripheral quantitative computed tomography and bone turnover markers such as osteocalcin, bone-specific alkaline phosphatase, procollagen type-1 N-terminal propeptide, and tartrate-resistant acid phosphatase-5b have been used to help predict osteoporotic fracture risk6. However, their application in clinical practice is limited in terms of medical cost and reimbursement. Therefore, because the aetiology of bone changes is complex in patients with CKD7, clinical risk factors should be considered, rather than relying solely on fragmented test data to predict osteoporotic fracture. Generally, factors other than BMD that affect osteoporotic fracture risk include advancing age, previous fracture, glucocorticoid therapy, family history of hip fracture, low body weight, excessive alcohol consumption, and current smoking11.Osteoporotic fracture in patients with chronic kidney disease (CKD) results in high morbidity and mortality12. Osteoporotic fractures are also associated with systemic dysregulation of calcium homeostasis, including intestinal calcium absorption, renal tubular calcium reabsorption, and bone demineralization13. Therefore, if patients with hypercalciuria excrete more calcium than they absorb, reduced bone density can occur. In fact, some previous studies reported that individuals with kidney stones were at higher risk for osteoporotic fracture17.Most kidney stones result from hyercalciuria, which is caused by systemic dysregulation of calcium homeostasis18. Interestingly, there is evidence that that the recurrence rate of kidney stones is lower in stone formers with reduced kidney function19. Therefore, the occurrence of kidney stones in patients with CKD may indicate severe dysregulation of calcium homeostasis. However, little is known about the association of kidney stones and bone health status in these patients. Therefore, it was hypothesized that the occurrence of kidney stones would be related with an increased risk of poor bone health in patients with CKD. In addition, we investigated whether the occurrence of kidney stones in these patients was associated with higher risk of osteoporotic fracture.Conceptually, CKD can prevent kidney stone formation because of significant reduction in urine calcium excretion, an important risk factor for stone formationThis study included 113 patients with stage 3–4 CKD and kidney stones. Of these, 56, 34, and 14 had nephrolithiasis, ureterolithiasis, or cystolithiasis, respectively. The rest were diagnosed with passed kidney stones. At study enrolment, 94 patients were diagnosed with asymptomatic kidney stones. In addition, 19 patients were diagnosed with symptomatic kidney stones. Of note, the median time interval between study enrolment and the diagnosis of symptomatic kidney stones was 9 months .p = 0.003), with higher body mass index (BMI)  and estimated glomerular filtration rate (eGFR) . In addition, use of vitamin D supplements  and calcium supplements  was more common in patients with kidney stones. However, serum phosphate concentration was lower in those with kidney stones. On the other hand, the proportion of osteoporotic fracture was higher in patients with kidney stones than in patients without kidney stones . Of note, there were 409 occurrences of osteoporotic fracture during follow-up, including 72 hip, 77 forearm, 29 humeral, 201 vertebral, and 30 other fractures. Especially, compared to patients without kidney stones, the relative frequency of hip and vertebral fractures was higher in patients with kidney stones  were men and the average age was 65.3 years. In addition, the mean eGFR was 38.9 ± 15.4 ml/min/1.73 mOf 49 osteoporotic fractures, 5 involved the hip, 11 the forearm, and 33 the vertebrae. In patients with kidney stones, osteoporotic fractures occurred in 24 and 9 patients after a diagnosis of asymptomatic or symptomatic kidney stones, respectively. Of note, there was no association between fracture site and symptomatic vs. asymptomatic kidney stones (Supplement Table p < 0.01) .During a mean follow-up duration of 64.7 ± 38.7 months, osteoporotic fracture occurred more often in patients with kidney stones 33, 29.2%) than in patients without kidney stones 16, 14.2%), resulting in rates of 5.56 and 2.62/100 patient-years, respectively .Risk factors for osteoporotic fracture are analysed in Table Compared to patients without kidney stones and with CKD stage 3, the multi-adjusted HR of osteoporotic fracture was highest in patients with kidney stones and CKD stage 4. In addition, the RERI and AP scales were positive, and the synergy index was >1, meaning a positive additive interaction effect on osteoporotic fracture between kidney stones and renal function . In line with the findings that fracture rates are elevated in patients with CKD, this rate is consistent with that reported by other studies21. Worldwide, about 80% of kidney stones are composed of calcium in the form of either calcium oxalate or calcium phosphate22. These stones develop when urine becomes supersaturated with insoluble compounds containing calcium, resulting from hypercalciuria23. The kidney plays a critical role in regulating serum calcium levels24. Calcium is both filtered and reabsorbed in the kidney24. If filtered calcium is abnormally increased or reabsorbed, the serum level is reduced and hypercalciuria occurs25. Therefore, reduced serum calcium levels stimulate increased calcium flow into plasma from bone to maintain equilibrium26. Eventually, hypercalciuria is associated with increased bone resorption, which leads to negative calcium balance and the loss of bone. Taken together, the presence of kidney stones, which are related to hypercalciuria, is considered to be the most common identifiable metabolic risk factor for osteopenia and osteoporosis. In fact, several studies showed that osteoporotic fracture occurred more frequently in patients with kidney stones than in the general papulation17. Meanwhile, the effect of CKD on the incidence of kidney stones has not been well studied. Conceptually, decreased filtered calcium caused by reduced GFR would lead to decreased supersaturation of calcium salts. In a longitudinal study of 3266 patients with kidney stones, Worcester et al. reported a decreased risk of recurrent kidney stones in patients with a single kidney compared to those with both kidneys intact19. In line with this finding, the prevalence of kidney stones in the present study was 4.5%, which was lower than in a previous report21.Although the prevalence of kidney stones has varied by region or time of survey, 8.8% was reported in the National Health and Nutritional Examination Survey for 2007 to 201024. In contrast to the passive calcium reabsorption that occurs in the more proximal nephron, active calcium reabsorption in the distal nephron is stimulated by parathyroid hormone (PTH)24. As kidney function decreases below a certain threshold value, PTH levels gradually increase28. Therefore, the development of kidney stones despite elevated PTH levels in patients with CKD may reflect a problem with PTH or calcium sensing receptor function in the renal tubule. Interestingly, Pubali et al. recently showed an association between PTH gene polymorphisms and increased risk of kidney stones29. Because PTH affects bone microarchitecture or turnover, most studies on PTH gene polymorphisms have focused on osteoporosis, bone mass, and bone size.The development of kidney stones in CKD despite preventive measures indicates that tubular calcium reabsorption is reduced. Approximately 60–70% of filtered calcium reabsorption occurs in the proximal convoluted tubule, with 20% in the loop of Henle, 10% in the distal convoluted tubule, and 5% in the collecting duct30. FRAX integrates clinical risk factor such as advancing age, previous fracture, glucocorticoid therapy, parental history of hip fracture, low body weight, current cigarette smoking, excessive alcohol consumption, rheumatoid arthritis, secondary osteoporosis, and BMD at the femoral neck31. However, this model does not include any adjustment of risk according to eGFR. In addition, although DXA is the most commonly used technique to assess BMD in patients with and without CKD, it cannot assess bone microarchitecture or bone turnover. Therefore, the presence of kidney stones can affect bone physiology and may be a clinical predictor of osteoporotic fracture in CKD patients.The Fracture Risk Assessment Tool (FRAX) is used to predict bone fractureThere are several limitations to our study. First, even though propensity score matching was used, this was a retrospective single-centre study based on a small number of CKD patients with kidney stones. Second, some patients who passed kidney stones might not have been diagnosed. Third, analysis of kidney stone composition was not performed. Fourth, parental history of hip fracture and previous fracture were not investigated. In addition, there was no measurement of BMD with DXA. Lastly, PTH gene polymorphisms or calcium sensing receptor function in the renal tubule were not also studied.In conclusion, there is a significant association between kidney stones in CKD patients and osteoporotic fracture after adjusting for most conventional fracture predictors except BMD. Accordingly, the presence of kidney stones should be considered a factor that contributes to osteoporotic fracture risk. A large-scale prospective trial is needed to confirm this conclusion.This study was performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (IRB) of Kangdong Sacred Heart Hospital, (Refs. Kangdong 2018-07-014). This was a retrospective medical record-based study and the study subjects were de-identified. The IRB waived the need for written consent from the patients.For this study, we initially selected 2624 patients with clinically stable stage 3–4 CKD at Kangdong Sacred Heart hospital between January 2006 and December 2017. Patients with the following conditions were excluded: Primary hyperparathyroidism (n = 2), liver cirrhosis (n = 35), haematologic disease (n = 19), metastatic cancer (n = 23), staghorn calculus associated with urinary tract infection (n = 18), fracture caused by major trauma such as a motor vehicle accident (n = 118), osteoporotic fracture before a diagnosis of symptomatic kidney stones (n = 6), and a follow-up period less than 1 year (n = 121). The remaining 2282 patients were included in this study . In addition, when renal function reached stage 3–4 in existing follow-up patients with early stage CKD, the above-mentioned imaging studies were repeated.This study included patients with symptomatic and asymptomatic kidney stones. Kidney stones were of 3 types, according to location: nephrolithiasis (in the kidney), ureterolithiasis (in the ureter), cystolithiasis (in the bladder). The diagnosis was confirmed with imaging studies. In addition, when kidney stones were not diagnosed on baseline imaging, additional studies were performed for symptoms of renal colic accompanied by urinary urgency, restlessness, haematuria, sweating, nausea, and vomiting during the follow-up period. Exceptionally, patients were diagnosed with kidney stones without radiologic confirmation, based on a clinical presentation consistent with having passed a stone.The study outcome was the occurrence of osteoporotic fracture, defined as fracture occurring with a fall from a standing height or less, without major trauma such as a motor vehicle accident. Osteoporotic fracture occurrence was defined as the first surgical or nonsurgical fracture requiring hospitalization or outpatient treatment during the study follow-up period. Of note, plain radiographs or magnetic resonance imaging (MRI) were available for each case of fracture and the diagnosis of fracture was confirmed based on the radiologist’s report. Excessive alcohol consumption was defined as drinking 3 or more units of alcohol daily. Current tobacco use was reported as smoking tobacco at the time of study enrolment. Vitamin D supplementation was defined as any use of alfacalcidol, cholecalciferol, or calcitriol. Phosphate binder included calcium acetate or calcium carbonate. Corticosteroid use was defined as a dose of 5 mg daily or more . Of note, patients who received a vitamin D supplement, calcium supplement, phosphate binder, or corticosteroids were defined as those treated for >3 months.The propensity score was determined using a multivariable logistic regression model with baseline covariates Table . Propenst-test for 2 groups. The categorical variables were expressed as frequencies and percentages and compared with either the chi-square test or Fisher’s exact test. Cumulative survival curves were generated using the Kaplan-Meier method to determine the association of kidney stones and osteoporotic fracture, and between-group osteoporotic fracture was compared using a log-rank test. The prognostic value of kidney stones for osteoporotic fracture was determined using multivariate Cox proportional-hazards regression analysis, which included all covariates with p values < 0.05 in the univariate analysis or conventional fracture risk factors other than BMD. To evaluate a potential interaction between kidney stones and renal function in osteoporotic fracture, patients were divided into 4 subgroups by kidney stones and renal function (CKD stage 3 vs. CKD stage 4). The relative excess risk due to interaction (RERI), the attributable proportion due to interaction (AP), and the synergic index (SI) were used to test an interaction on an additive scale32. Both the point estimation and 95% CI of RERI, AP, and SI were assessed using a method accounting for asymmetric distribution of confidence limits for risk ratio33.Statistical analyses were performed using SPSS 19.0 . The Kolmogorov-Smirnov test was used to test the normality of continuous variables. The normally distributed variables were expressed as mean ± SD and compared with Student’s Kidney Stones and Risk of Osteoporotic Fracture in Chronic Kidney Disease


During lumbar spine surgery, patients are placed in the prone position for surgical access. The prone position has various effects on cardiac and pulmonary function, including a decreased cardiac index (CI), decreased dynamic lung compliance (Cdyn), and increased peak inspiratory pressure (Ppeak). In this study, we compared the volume-controlled ventilation mode (VCV) and pressure-controlled ventilation with volume guaranteed mode (PCV-VG) based on hemodynamic and pulmonary variables in the prone position during lumbar spine surgery.Thirty-six patients scheduled for lumbar spine surgery in the prone position were enrolled in this prospective, randomized clinical trial. The patients were randomly assigned to receive VCV or PCV-VG. Hemodynamic variables, respiratory variables, and arterial blood gases were measured in the supine position 15 min after the induction of anesthesia, 15 min after placement in the prone position, 30 min after placement in the prone position, and 15 min after placement in the supine position at the end of anesthesia.p = 0.045). The Cdyn values in the VCV group were lower than those in the PCV-VG group (p = 0.040).The hemodynamic variables and arterial blood gas results did not differ significantly between the two groups. Lower Ppeak values were observed in the PCV-VG group than in the VCV group . The initial registration date was 6/18/2018.The study was retrospectively registered at  The prone position is commonly required to enable surgical access during lumbar spine surgery. When a patient moves into the prone position, inferior vena cava obstruction causes reduced venous return and increased thoracic pressure results in reduced left ventricular compliance, leading to a decreased cardiac index (CI) . PulmonaThe volume-controlled ventilation mode (VCV) is commonly used during general anesthesia: the minute ventilation is fixed and airway pressure is influenced by pulmonary resistance or compliance . The preIn this randomized study, we tested the null hypothesis that VCV or PCV-VG does not affect hemodynamic or pulmonary variables during lumbar spine surgery in the prone position. The primary outcome of this study was Ppeak. The secondary outcomes were lung compliance and hemodynamic variables including cardiac output (CO), CI, stroke volume (SV), and stroke volume variation (SVV).2), hypotension (systolic blood pressure < 100 mmHg), bradycardia (heart rate < 60 bpm), uncompensated cardiologic disease , hypoxia (PaO2 < 60 mmHg or SpO2 < 90%), uncontrolled asthma, or chronic obstructive pulmonary disease (forced expiratory volume in 1 s < 60%) were excluded. Patients who were younger than 20 years or older than 70 years were also excluded. This study was registered at ClinicalTrials.gov (NCT 03571854). The study was conducted in accordance with the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement [This study was approved by the Institutional Review Board of Hallym University Sacred Heart Hospital. After written informed consent was obtained from all participants, 36 patients who were scheduled for lumbar spine surgery in the prone position were enrolled. Patients with morbid obesity (body mass index > 30 kg/m2) before the induction of anesthesia. Anesthesia was induced with remifentanil (0.1–0.2 μg/kg/min), propofol (1.5–2 mg/kg), and rocuronium (0.6 mg/kg), and maintained at a fractional inspired oxygen concentration of 0.5 with sevoflurane (2.0–2.5 vol%), remifentanil (0.05–0.3 μg/kg/min), and vecuronium (0.03–0.05 mg/kg/h). The patients were ventilated with a Datex-Ohmeda Ventilator (S/S AVANCE) and randomly assigned to receive either VCV (n = 18) or PCV-VG (n = 18) using a computer-generated randomization method. The tidal volume in both groups was set to deliver 8 mL/kg of ideal body weight. The respiratory rate (RR) was adjusted to maintain an end tidal CO2 (ETCO2) level of 33–38 mmHg, and the inspiratory to expiratory time (I:E) ratio was 0.5. After the induction of anesthesia, a 20 G catheter was inserted into the radial artery to monitor continuous arterial pressure and connected to the FloTrac®/Vigileo system  for the continuous monitoring of variables, including CO, CI, SV, stroke volume index (SVI), and SVV.All patients fasted for 8 h before surgery and were premedicated with intramuscular glycopyrrolate (0.2 mg). In the operating room, patients were monitored by non-invasive blood pressure, electrocardiography, and pulse oximetry .Hemodynamic variables, respiratory variables, and arterial blood gases were measured in the supine position 15 min after the induction of anesthesia, 15 min after placement in the prone position, 30 min after placement in the prone position, and 15 min after placement in the supine position at the end of anesthesia. The measured hemodynamic variables included mean arterial pressure (MAP), heart rate (HR), CO, CI, SV, SVI, and SVV. Respiratory variables included RR, Ppeak, mean inspiratory pressure (Pmean), SpOAs there have been no previous studies comparing the effects of PCV-VG and VCV during surgery in the prone position, the sample size for this study was determined in a pilot study. The results indicated a mean difference in Ppeak between the two modes of 10% . Assuming a 20% dropout rate, 18 patients were included in each group in this study.t-test or Mann-Whitney U test; p-values < 0.05 were considered statistically significant. Statistical analyses were performed using the Statistical Package for the Social Sciences version 24.0 .All data are presented as the median (interquartile range) or number of patients. Hemodynamic and respiratory data were analyzed with a repeated-measures analysis of variance, and differences between groups at the same time point were analyzed with the two-sample p = 0.045, Fig. p = 0.040, Fig. A total of 36 patients were enrolled in this study and a CONSORT flow diagram is shown in Fig. HR decreased after placement in the prone position in both groups, but no significant intergroup difference was present. CO and CI did not differ significantly between groups, while the CO and CI values decreased 15 min after placement in the prone position Table . The bloIn the present study, we compared the effects of the VCV and PCV-VG on hemodynamic and pulmonary variables in the prone position. In VCV, the ventilator delivers a target volume with a constant flow and the airway pressure increases in a linear manner. This approach ensures minute ventilation regardless of airway compliance but cannot control airway pressure . CompareSeveral studies have examined the effects of the PCV-VG compared with conventional modes (VCV or PCV). In thoracic surgery with one-lung ventilation, PCV-VG led to lower Ppeak, peak plateau pressure, and Pmean values compared with VCV , 11. SimSpine surgery is commonly performed with patients in the prone position. In respiratory physiology, Ppeak increases and Cdyn decreases as increased intra-thoracic pressure and abdominal pressure compromise diaphragm movement when a patient is turned to the prone position , 13, 14.Pmean correlates with alveolar ventilation and improved oxygenation . AlthougIt is known that the CI decreases when a patient moves in the prone position. This is caused by reduced venous return and increased intra-thoracic pressure, which results in decreased arterial filling and reduced ventricular compliance . DharmavIn the present study, the CO and CI values measured 15 min after placement in the prone position were lower compared with the same values measured in the supine position. The SV values did not significantly change as patients were positioned on the Jackson table, so it is thought that the decreased CO and CI in the prone position may have been caused by a decreased HR, rather than decreased preload or increased afterload.It can be expected that differences in Ppeak between VCV and PCV-VG will affect pleural pressure, inducing changes in the cardiovascular response . HoweverThe present study has several limitations. First, although the FloTrac®/Vigileo system is widely used in anesthesia, it is an uncalibrated pulse contour analysis and may be less accurate under conditions such as sepsis or reduced systemic vascular resistance . GrensemIn conclusion, PCV-VG provided a lower Ppeak and improved Cdyn compared with VCV, and was not associated with significant differences in CO, CI, SV, SVV, and oxygenation. These results show that PCV-VG may be an effective alternative mode of mechanical ventilation for patients in the prone position during lumbar spine surgery. Additional studies are required to evaluate the effects of Ppeak on postoperative patient outcome.


The alpha-adrenergic agonist phenylephrine is often used to treat hypotension during anesthesia. In clinical situations, low blood pressure may require prompt intervention by intravenous bolus or infusion. Differences in responsiveness to phenylephrine treatment are commonly observed in clinical practice. Candidate gene studies indicate genetic variants may contribute to this variable response.k-means clustering was conducted on clean data containing 4130 patients based on phenylephrine infusion rate and blood pressure parameters, to identify potential phenotypic subtypes. Genome-wide association studies (GWAS) were performed against average infusion rates in two cohorts: phase I (n = 1205) and phase II (n = 329). Top genetic variants identified from the meta-analysis were further examined to see if they could differentiate subgroups identified by k-means clustering.Pharmacological and physiological data were retrospectively extracted from routine clinical anesthetic records. Response to phenylephrine boluses could not be reliably assessed, so infusion rates were used for analysis. Unsupervised P < 1 × 10−6 were associated with phenylephrine infusion rate. Only rs11572377 with P = 6.09 × 10−7, a 3′UTR variant of EDN2, encoding a secretory vasoconstricting peptide, could significantly differentiate resistant from sensitive groups (P = 0.015 and 0.018 for phase I and phase II) or resistant from pooled sensitive and intermediate groups (P = 0.047 and 0.018).Three subgroups of patients with different response to phenylephrine were clustered and characterized: resistant (high infusion rate yet low mean systolic blood pressure (SBP)), intermediate (low infusion rate and low SBP), and sensitive (low infusion rate with high SBP). Differences among clusters were tabulated to assess for possible confounding influences. Comorbidity hierarchical clustering showed the resistant group had a higher prevalence of confounding factors than the intermediate and sensitive groups although overall prevalence is below 6%. Three loci with EDN2, has robust biological relevance to vasoconstriction by binding to endothelin type A (ETA) receptors on arterial smooth muscle cells, further functional as well as replication studies are necessary to confirm this association.Retrospective analysis of electronic anesthetic records data coupled with the genetic data identified genetic variants contributing to variable sensitivity to phenylephrine infusion during anesthesia. Although the identified top gene, The online version of this article (10.1186/s12916-019-1405-7) contains supplementary material, which is available to authorized users. It is one of the most commonly used drugs for treatment of intraoperative hypotension [Phenylephrine is a very selective αotension –4. PatieADRB2 on hemodynamic response [1-adrenergic receptor agonist, phenylephrine has a moderate β-agonist activity at higher doses [ADRB2, encoding the β2 adrenoreceptor, had a much higher sensitivity to phenylephrine than non-carriers [ADRA1B, encoding α1 adrenergic receptor 1B subtype, and phenylephrine response was evaluated [ADRA1A, encoding α1 adrenergic receptor 1A subtype, on phenylephrine response. Although all these candidate gene studies showed some promising connection between pharmacodynamic genes and drug response, the significance of the association has been limited by sample size, number of interrogated genetic variants, definition of responsiveness (response or non-response as a binary trait), magnitude of variation in response (quantitative trait), mixture of vasopressors, and hypotheses. Genome-wide association studies (GWAS) employ large patient cohorts and subsequent fine-mapping techniques that are hypothesis-agnostic and thus not limited to preconceived ideas of the genes involved in the phenotype based on prior knowledge.While some work has been done looking at genetic influence of response , 6, veryer doses , 8. Sevecarriers . The Argcarriers . Howevercarriers . The assvaluated . rs10070valuated . There wIn clinical situations, phenylephrine is most often administered as boluses, less often by infusion. An immediate increase of BP after a bolus, usually prompt in onset and lasting for minutes, could be used to evaluate responsiveness to phenylephrine. This requires frequent BP measurements during the effect window, a requirement not satisfied by the available research data extracted from clinical anesthesia records. Alternatively, intravenous (IV) infusion rate (dose) could be used to estimate phenylephrine sensitivity. Infusion rates are determined empirically by clinicians, adjusted dynamically as needed by changing conditions, and subject to numerous unaccounted determinants  to maintain situationally appropriate blood pressures. Infusion rates can be quite variable while being titrated to effect, then rather stable for long periods after completion of initial adjustments. With a large patient cohort, individual variations are expected to be randomly distributed relative to the genetic variations.Geisinger is an integrated healthcare provider located in central and northeastern Pennsylvania and southern New Jersey, having an electronic health record (EHR) system which captures a median of 14 years of comprehensive electronic records for participants in the MyCode® Community Health Initiative (MyCode) which include but are not limited to patients’ demographic features, primary diagnoses and co-morbidities, laboratory measurements, prescriptions, vital signs, and surgical procedure logs . IntraopIn this study, we present the results of the first GWAS for phenylephrine response defined by phenylephrine infusion rate using real-world EHR data.This study population consisted of 12,688 individuals with available electronic anesthesia records from the Geisinger de-identified EHR database who met the inclusion criteria described in more detail below. We received an exemption from the institutional review board (IRB) for a non-human subject study as all the EHR data were de-identified. For the genetic study, we received approval from the IRB at Geisinger and the MyCode Governing Board. All MyCode participants provide a consent that allows their clinical and genomic data to be used for health-related research. Details of the consenting process are described elsewhere . ApproxiIn Geisinger clinical practice, as at many other institutions, phenylephrine is typically the first-line vasopressor for treatment of hypotension during anesthesia. However, there are no standardized phenylephrine infusion guidelines, BP targets, or practices for cases in this opportunistic cohort. Pharmacy prepares standard concentrations of phenylephrine for infusions. Choice and management of phenylephrine infusions was entirely at the discretion of anesthesia clinicians. General anesthesia predominates for surgeries at Geisinger, although spinal and regional anesthetics are employed with and without general anesthesia. Data de-identification and extraction were conducted by Geisinger’s Phenomic Analytics & Clinical Data Core. Patient information of those who had electronic anesthesia records between July 2012 and November 2016 excluding cesarean sections and trauma cases was obtained. The following de-identified data elements were requested: surgery duration; anesthetic agents and other intraoperative drugs, doses and total quantity of phenylephrine; start and end time of each phenylephrine infusion; phenylephrine infusion rates; blood pressures; age and weight at the time of surgery; International Classification of Disease v. 9 (ICD-9) coded diagnoses; and demographics. The extracted anesthetic record data originated from multiple Geisinger outpatient and inpatient sites distributed across a large geographical area. There was no selection for patient characteristics, types of procedures, surgical departments, or anesthetic techniques.Analyses employed SBP because it is the most consistently present blood pressure parameter and has larger changes in response to phenylephrine treatment than mean artery pressure (MAP) or DBP, though MAP may be a more robust physiological measurement and better correlated between invasive and non-invasive BP measurements. We removed obvious errors in the data by identifying values that were not representative of the measurement, such as implausible values , and extreme SBP values (SBP < 20 mmHg or SBP > 200 mmHg) as they were less likely to be caused by genetic factors, but more likely to be data errors or artifacts, such as arterial line flushes, disconnections, or physiological extremis. Patients who had ephedrine and/or phenylephrine boluses during phenylephrine infusion, patients who had short infusion periods (< 10 min), or few blood pressure measurements during the infusion interval (< 3 data points) were also excluded from further analysis. Median count for SBP measurements per patient is 16. These quality-checked data were then used for data modeling  were evaluated using three key features related to phenylephrine response: mean and standard deviation (SD) of systolic blood pressure (SBP) during infusion period and average infusion rate of phenylephrine. We also evaluated the k-means clustering on a broader set of features including weight, age, and infusion duration. Data standardization and k-means clustering were performed using Python (2.7.14) scikit-learn library (0.19.1).Empirical observation discerns three types of response to phenylephrine infusion: normal or high BP with low infusion rate (“sensitive”), correction of severe hypotension but still low BP with low infusion rate (“intermediate”), and ameliorated yet still low BP requiring high infusion rate (“resistant”). A “fourth” hypothetical cluster having high BP at high infusion rates is not represented in the data because clinicians rarely need to use phenylephrine to increase already normal or high blood pressures. P value < 0.00625 (0.05/8) was considered significant after the Bonferroni correction for multiple comparisons.To determine whether there were statistical differences in clinical features between clustering derived subgroups, chi-square tests were used for categorical data, and one-way ANOVA was used for continuous data. These statistical analyses were performed using GraphPad Prism (7.04). The ICD-9 codes were used at the 3-digit level. For example, individuals with the codes 203.01  and/or 203.12  would be evaluated in the same group 203 (multiple myeloma and immunoproliferative neoplasms). Patients with the same truncated 3-digit codes on at least three different dates were considered to have reportable evidence for the 3-digit disease code class. Diseases with prevalence ≥ 0.5% in all the three groups were clustered via hierarchical clustering using Euclidean distance and average linkage and plotted in a heatmap using R (version 3.4.3). Chi-square test was used to evaluate the significance of the difference among subgroups.P < 10−7) were removed. At last, there were 4,929,806 SNPs in phase I and 2,978,370 SNPs in phase II included in the analysis. One of paired of individuals with first- or second-degree relatedness, as determined by IBD analysis were removed from analysis. PLINK 1.9 [Genotyping was performed in batches on the Illumina Infinium OmniExpress Exome array and GSA-24v1-0 array at different time for phase I and phase II cohorts, respectively. Genotypes for both cohorts were imputed to HRC.r1-1 EUR reference genome (GRCh37 build) separately using the Michigan Imputation Server . VariantLINK 1.9  was usedk-means clustering, were removed from further analyses. The mean values of the SBP, age, and weight for the other 77 patients who had concordant cluster associations from multiple surgeries were used to avoid non-independent measurements in the association test. Finally, 1574 patients were subject to genetic analyses. A linear regression model for average infusion rate with full set of covariates without interaction terms was conducted first to decide which covariates to adjust in the genetic association test. Covariates that were evaluated included age, sex, weight, mean SBP, SD of SBP, anesthesia type, and comorbidities that may affect the pharmacokinetics and blood pressure, including diabetes, hypertension, lipid metabolism disorders, overweight and obesity, ischemic heart disease, heart failure, and cardiac dysrhythmias. Only age, sex, weight, mean of SBP, and SD of SBP were significantly associated with the infusion rate , concurrent confounding ephedrine and/or phenylephrine bolus injections during the infusion period, blood pressure values that were not exclusively obtained by either invasive or non-invasive measurements, fewer than three SBP measurements during phenylephrine infusion, implausible infusion rate units, and missing body weight , mean SBP (mmHg), and SD of SBP. SD of SBP reflects the blood pressure variability during the infusion period. When two clusters were considered (k = 2), the separation was made by blood pressures but not by average infusion rate , patients were classified into three categories that can be described as intermediate responders , having low mean SBP under low infusion rate of phenylephrine; resistant responders , requiring higher infusion rate to maintain low mean SBP; and sensitive responders , having higher mean SBP with low infusion rates  and higher body weight (P = 0.0016) than the intermediate and the sensitive groups, suggesting that sex and body weight could possibly be predictors of phenylephrine response and should be included as confounding factors in the association study. One of the key pharmacokinetic parameters, volume of distribution (VD) of a drug, which is the circulation volume for phenylephrine infusion, could be significantly affected by body weight. The mean age of sensitive responders was significantly higher than that of intermediate (P = 1.759 × 10−12) and resistant patients (P = 2.2 × 10−16).Since responsiveness can be affected by multiple genetic or non-genetic factors, the clinical features in each subgroup were further compared by chi-square test or one-way ANOVA for categorical and quantitative features, respectively Fig. . The meaP = 0.00023), heart failure (P = 0.003), chronic kidney disease (P = 0.02), overweight (P = 0.04), and disorders of fluid-electrolyte and acid-base balance (P = 0.04), suggesting more confounding factors and severity of illness in the resistant group. These could reflect physiological alterations or more clinically significant compromise in these patients, requiring more aggressive treatment of hypotension. The overall calculated comorbidity prevalence was low (< 6%) across all three subgroups. This might explain why comorbidities were not significant covariates in the full model on phenylephrine infusion rate  were identified to be associated with the phenylephrine average infusion rate after a meta-analysis. Figure F2RL2 and IQGAP2. This SNP is in complete linkage disequilibrium (LD) with rs193230021 and rs116836657, both of which are located at 3′UTR for F2RL2. rs77080086, the second top hit, is an intronic variant in PDE4B that encodes an enzyme that specifically hydrolyzes cAMP, a critical step in the β-adrenergic receptors signaling [EDN2, encodes endothelin-2, a secretory vasoconstrictive peptide which causes vasoconstrictions by tightly binding to smooth muscle ETA receptors [All patients included in this GWAS have genetically verified European ancestry, a characteristic of the Geisinger regional population that may not be generalizable. We applied a linear regression model to identify the potential confounding factors related to average infusion rate  and Gly16Arg  polymorphisms in the ADRB2 and phenylephrine response [ADRA1A, ADRA1B, and ADRB2. Only 8 SNPs in an intron of ADRA1A showed a nominal significant association (P < 0.05) after meta-analyses  and resistant versus sensitive + intermediate groups (P = 0.047 and 0.0182) in both phase I and phase II cohorts. The regional association plot for EDN2 and the boxplot for infusion rates by rs11572377 genotypes are shown in Fig. We performed association tests using binary traits by comparing the resistant group versus the sensitive group alone or the pooled sensitive + intermediate groups. We also evaluated the interaction of SNPs with body weight by adding an interaction term in the regression models. Results are summarized in Table P > 0.05), age (data not shown), and sex (data not shown), suggesting that rs11572377 is an independent genetic factor associated with phenylephrine response.There was no significant interaction between the genotype of rs11572377 and confounding factors such as body weight  in the three subgroups identified by k-means clustering. Only rs11572377 at the 3′UTR of EDN2 was significantly different in both the extreme cases (sensitive vs resistant) and all cases (resistant vs sensitive + intermediate) in phase I and phase II cohorts (P < 0.05). There is no significant interaction between this genotype and confounding factors such as body weight, age, or sex, suggesting that rs11572377 is an independent genetic factor associated with phenylephrine response.In this study, we leveraged comprehensive EHR data from Geisinger and applied an unsupervised machine learning approach to classify patients who had quantifiable phenylephrine infusion rates during surgery into three subcategories: resistant (high infusion with rate low BP), intermediate (low infusion rate with low BP), and sensitive (low infusion rate with high BP). Comorbidity hierarchical clustering showed the resistant group had a higher prevalence of confounding factors including heart failure, chronic kidney diseases, and acid-base imbalance, and were distinct from the intermediate and sensitive groups. Meta-analysis of the summary statistics from the phase I and phase II GWAS identified 12 independent loci with es Table . We furtEDN2 encodes endothelin-2, a secretory vasoconstrictive peptide that can cause potent long-lasting vasoconstriction by binding to ETA receptors on arterial smooth muscle cells. Genetic polymorphisms of EDN2 quantitatively associated with pretreatment DBP in hypertensives but not in normotensive individuals [A receptors [A and ETB receptors as endothelin-1, it exhibits a distinct mechanism and pathway affinity for vasoconstriction [ividuals , 27. Seveceptors –30. Diffeceptors –33. Althtriction , 34. Furtriction .There are some limitations to the study. First, it would have been preferable to use bolus injections of phenylephrine for analysis, as this represents a more usual clinical scenario, and the transient BP response is often clearly evident in routine anesthesia records. However, the available de-identified clinical data derived from anesthesia records did not incorporate all of the expected BP data. The blood pressures in the de-identified research dataset were not reliably frequent enough to assess blood pressure responses to phenylephrine boluses. Thus, infusion rates were used as a surrogate for assessment of phenylephrine sensitivity phenotypes since continuous infusions would span longer time intervals between BP values. Compared to previous candidate gene studies assessing phenylephrine sensitivity using the linear variable differential transformer dorsal hand vein technique , 12, 36,P = 0.258) on the association between EDN2 SNPs and phenylephrine infusion rate after adding the interactive term (rs11572377 × drug) in the linear regression model.Second, this study incorporated data from the entire range of anesthetics for all varieties of surgical procedures; many potentially confounding variations of patient condition and surgical requirements are unidentified and assumed to be randomly distributed across the clusters. Phenylephrine infusion rate could be potentially influenced by many nongenetic factors during anesthesia which could not be accounted for in the analyses. These include episodic blood loss, intravenous fluid boluses versus maintenance infusions, stimuli from surgery, long-term comorbidities, and pre or concurrent medication such as angiotensin converting enzyme inhibitors (ACEI). This could explain in part the observation that 97 patients who had two or more surgical episodes had inconsistent cluster assignment. The number of patients was insufficient to explore this hypothesis, but analysis of this subgroup could be used to explore potential gene by environment interactions impacting response to phenylephrine. Our preliminary analyses showed that premedication with ACEI or angiotensin II receptor blockers as a covariate have no significant impact , a type 1 error rate of 1 × 10−4 for a suggestive significance with a two-sided test, on the continuous trait with mean ± SD of average infusion rate as 37.33 ± 19.7. Our sample size of 1534 from phase I and phase II samples had more than 80% power to identify a significant association when the minor allele frequency was equal to 0.017. Genotyping and exome sequencing of additional consented participants will increase size of potential analytic cohorts. With larger cohorts, the opportunity to select more homogeneous groups for genetic analysis may resolve issues confounding this preliminary investigation.Third, limitation to cases with phenylephrine infusions curtailed the number of cases available for analysis. We removed approximately 70% of the cases initially eligible in this study to minimize the effects of heterogeneity in the patient population and obvious major confounding factors. This additional filtering process improved homogeneity, but at the expense of a significant decrease in sample size. Analysis of genomic associations limited to cases having phenylephrine infusions is potentially biased by selection of records for more acutely compromised clinical cases with variations in tendency to hypotension under volatile general anesthetics and a wide variety of surgical procedures. Vasopressor infusions tend to be used when other interventions such as intravenous volume infusion are inadequate to maintain correction of hypotension. However, the approach to select extreme phenotypes may identify genetic factors with bigger effect size, thus increasing statistical power. To quantify the potential impact of the decreased sample size, we conducted a power test using Quanto, given the main effect of βFourth, phenylephrine infusion is frequently used to treat hypotension induced by spinal anesthesia in cesarean section , 38. We This preliminary investigation has exposed numerous challenges and opportunities to improve the extraction of appropriate characteristics from routine clinical EHR, so that functional phenotypes can be better defined and distinguished as necessary adjuncts for genomic analysis. Improving extraction of details available in routine anesthesia records will greatly improve definition of functional phenotypes for future studies, likely to increase events available for analysis by an order of magnitude. Aggregating data from numerous institutions has been a major challenge of the Multi-Center Perioperative Outcomes Group (MPOG) due to differences in participating organization practices and data formats –43. Yet,k-means clustering, we identified three subgroups of patients who were “resistant,” “intermediate,” and “sensitive” to phenylephrine infusion. Through meta-analyses of the phase I and phase II GWAS, we identified rs11572377, a 3′UTR variant of EDN2, as one of the top hits associated with differential response to phenylephrine infusion rate. This study demonstrated the EHR data can be a powerful resource for anesthesiology research. Future studies with more detailed extraction of data from clinical anesthesia records and other available clinical data will help to improve phenomic characterization for research and help with understanding of phenylephrine response.In this study, we described a novel strategy to analyze “real-world” EHR data followed by GWAS to identify genetic factors associated with phenylephrine infusion rate during anesthesia. Through Additional file 1:Table S1. The association of potential covariates with average infusion rates using a linear model. (DOCX 13 kb)Additional file 2:Figure S1.k-means clustering based on phenylephrine infusion rate, mean and SD values of SBP when k = 2. (DOCX 50 kb)Additional file 3:Figure S2. Evaluating k-means clustering on different feature combinations (DOCX 418 kb)Additional file 4:Table S2. Summary of SNPs in ADRA1A that showed nominal association (P < 0.05) with phenylephrine infusion rate. (DOCX 16 kb)


It has been reported that people living with HIV in West Africa exhibited the highest risks for chronic kidney disease (CKD) in the world. Here, we aimed at determining the CKD frequency and changes in kidney function during antiretroviral treatment (ART) in a large cohort of HIV-patients followed in Burkina Faso.2 at two consecutive measurements at least 3 months apart. The factors associated with eGFR decline or CKD were identified by mixed linear regression and Cox regression, respectively.We included ART-naive adults who initiated ART at the Day Care Unit of the Souro Sanou University Hospital between 01/01/2007 and 12/31/2016. We assessed the estimated glomerular filtration rate (eGFR) by serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. Following the K/DOQI recommendations, CKD was defined as eGFR < 60 ml/min/1.73m2 and 93 (3%) patients exhibited eGFR < 60 ml/min/1.73m2. The lowest-performing progressions of eGFR during the first year of ART were observed in patients with 40-49 yr. age range , age ≥ 50 yr.  and high blood pressure (HBP)  at ART initiation. Regarding the ART exposure in patients with normal baseline eGFR, zidovudine (AZT) with protease inhibitor (PI) , tenofovir (TDF) + PI , TDF without PI , stavudine (d4T) + PI  and d4T without PI  were associated with poorer eGFR progression. The prevalence of CKD was 0.5% and the incidence was 1.9  cases/1000 person-years. The risk of CKD was higher in patients with HBP , 40-49 yr. patients , ≥50 yr. patients  and patients exposed to abacavir (ABC) or didanosine (ddI) based ART .Three thousand, one hundred and thirty-eight patients (72% women) were followed for a median (IQR) of 4.5(2.2–6.9) years. At baseline, median eGFR (IQR) was 110.7(94.4–128.4) ml/min/1.73mOur findings do not confirm the high risk of CKD reported in previous studies of West Africans with HIV, but support the recommendations for early initiation of ART and close kidney function monitoring in patients with HBP or aged ≥40 yr. Kidney impairments in HIV-infected patients are a major cause of morbidity and mortality –3. In soApart from traditional risk factors for CKD such as aging, high blood pressure (HBP) and diabetes, the increased-risk for CKD in PLHIV may be explained by HIV and ART-related factors –11. SeveKidney Disease Quality Outcome Initiative (K/DOQI) which defines CKD by the presence of kidney damage or GFR < 60 ml/min/1.73 m2 for at least 3 months  × 1.212 [if black]), where Scr is serum creatinine)  times (p = 0.004) and 4.5  times (p = 0.009) higher in the 40-49 yr. and ≥ 50 yr. age groups. Compared to patients who were on AZT-containing therapy without PI, those who were exposed to therapy containing ABC, ddI or both were 13.1  times (p < 0.001) more likely to develop CKD. . The analyses therefore focused on 3124 patients who contributed to 14,318 person-years of follow-up. A total of 27 incident cases of CKD were recorded, namely 1.9  cases per 1000 person-years. In a multivariable analysis, the risk of CKD was 4.3  times higher in patients with HBP  at ART initiation. Baseline predictors for poor kidney function progression after initiation of ART were older age (≥40 yr), HBP and low CD4 counts (< 100 cells/μl). Exposure to treatments containing TDF or d4T, especially when associated with PI was also a predictor for poor kidney function evolution. The incidence of CKD was low (1.9 per 1000 patient-years) in our cohort as was CKD prevalence (0.5%). Patients over 40 and those with HBP were more likely to progress to CKD during follow-up. Patients who received ABC for their kidney impairment were also more likely to progress to CKD.Consistently with the findings of previous reports in cohorts of adults initiating ART, we found that baseline eGFR was a strong predictor of subsequent changes and eGFR increased in individuals with impaired kidney function at treatment initiation , 29, 30.Of the three equations commonly used to estimate eGFR, the Cockcroft and Gault equation is the least accurate with a lower eGFR than those estimated by the MDRD and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations . TherefoBased on the confirmed CKD as defined (stage 3a-5 on 2 measurements), two African studies reported different prevalences. One in Burundi with a prevalence close to what we observed (1.7% = 5/300)  and the Based on the unconfirmed CKD defined by an eGFR < 60 on a single measurement, we find more studies in Africa. In our study, the prevalence of baseline eGFR< 60 is 3%. This prevalence is comparable to the prevalence found in a study that included Zimbabwe and Uganda patients (3.1%)  and in aStudies in Africa on CKD incidence among PLHIV are based on unconfirmed CKD , 43. To In accordance with our results, most studies found that older age and HBP are predictors of poor kidney function progression and of CKD , 29, 43.In this study, we cannot rule out the contribution of a selection bias to explain the low prevalence and incidence of CKD in the cohort. Indeed, we showed that patients who were not included in the analysis because they died or were lost to follow-up before initiating ART or before having eGFR follow-up data while on ART, were more likely to have eGFR< 60 at baseline. This observation supports a selection or survival bias that would lead to underestimation of CKD prevalence and incidence in the population. This selection bias may have had a higher impact in this study compared to other studies because of the retrospective design of the study with less frequent biological monitoring. Another limitation of our study is the unavailability of certain data, including proteinuria and viral load at initiation of antiretroviral therapy. Similarly, information on concomitant medications including possible nephrotoxic drugs , hepatitis C or a history of kidney disease were not available. This may have introduced confounding biases into our analyses.Our study reports a CKD prevalence of 0.5% and an incidence of 1.9 per 1000 person-years in a cohort of PLVIH from Burkina Faso. These numbers are lower than previously reported. The retrospective design of our study with less frequent measurements of eGFR and the process of selecting our study population might have underestimated the CKD frequency in our cohort. HBP and age ≥ 40 yr. at ART initiation are both risk factors for CKD and predictors for poor eGFR progression during ART. Patients who started ART with kidney impairments had their kidney function improved but never recovered to an eGFR level similar to those who started ART with normal kidney function. In patients who started ART with a normal kidney function, exposure to ART containing both TDF and PI induced the most important loss of eGFR  during the first year of treatment.In conclusion, our results support the recommendations for early ART initiation before the onset of kidney impairment, which is concomitant with immunosuppression. We also suggest close kidney function monitoring in PLHIV with HBP and those aged ≥40 yr. The use of treatment containing both TDF and PI should be cautious in patients with renal risk. Finally, a prospective cohort study will be necessary to better estimate the prevalence and incidence of CKD among PLHIV in Africa.


The mean arterial blood pressure (MAP), heart rate (HR), end-tidal CO2 (EtCO2), central venous pressure (CVP), stroke volume (SV), CO, pulse pressure variation (PPV), stroke volume variation (SVV) and systemic vascular resistance (SVR) were recorded continuously. The values at the moment before administration of phenylephrine and 5(T5) and 10(T10) min thereafter were compared. After phenylephrine, the mean(SD) MAP, SV, CO, CVP and EtCO2 increased by 34(13) mmHg, 11(9) mL, 1.02(0.74) L min−1, 3(2.6) mmHg and 4.0(1.6) mmHg at T5 respectively, while both dynamic preload variables decreased: PPV dropped from 20% at baseline to 9% at T5 and to 13% at T10 and SVV from 19 to 11 and 14%, respectively. Initially, the increase in MAP was perfectly aligned with the increase in SVR, until 150 s after the initial increase in MAP, when both curves started to dissociate. The dissociation of the evolution of MAP and SVR, together with the changes in PPV, CVP, EtCO2 and CO indicate that in patients with anesthesia-induced hypotension, phenylephrine increases the CO by virtue of an increase in cardiac preload.Induction of general anesthesia frequently induces arterial hypotension, which is often treated with a vasopressor, such as phenylephrine. As a pure α-agonist, phenylephrine is conventionally considered to solely induce arterial vasoconstriction and thus increase cardiac afterload but not cardiac preload. In specific circumstances, however, phenylephrine may also contribute to an increase in venous return and thus cardiac output (CO). The aim of this study is to describe the initial time course of the effects of phenylephrine on various hemodynamic variables and to evaluate the ability of advanced hemodynamic monitoring to quantify these changes through different hemodynamic variables. In 24 patients, after induction of anesthesia, during the period before surgical stimulus, phenylephrine 2 µg kg The ultimate goal of hemodynamic management is to maintain adequate tissue oxygen delivery to the different end-organs . Surgica1, increasing the systemic vascular resistance (SVR) and arterial pressure [1 receptor activity is acknowledged scientifically, in most clinical conditions, phenylephrine is considered to increase cardiac afterload but not cardiac preload. In patients with life threatening septic shock, norepinephrine has been shown to increase venous return in case of preload dependence [1-adrenergic receptor stimulation—either by phenylephrine or norepinephrine—also decreases venous capacitance, which could in turn increase cardiac preload and SV [Phenylephrine is a direct α-adrenergic receptor agonist, predominantly αpressure . While vpendence , 5. Nevependence , the α1-d and SV . It has d and SV . When thd and SV . We hypoThe aim of this study was to differentiate the chronicity of the changes in cardiac preload and CO after a single administration of phenylephrine and to assess the ability of advanced hemodynamic monitoring to quantify these changes through different hemodynamic variables.This prospective interventional study was approved by the institutional review board and was registered at clinicaltrials.gov . The manuscript adheres to the applicable STROBE guidelines. After written informed consent was obtained, a total of 24 adult patients, scheduled for elective laparoscopic sigmoidectomy were included  with an O2/air mixture (FiO2 0.6) and a PEEP of 4 cm H2O. During the study period, the ventilatory settings were unchanged. A radial artery was cannulated using a 20 G catheter and connected with a disposable ProAQT transducer from the Pulsioflex monitor —all measurements were conducted with the same Pulsioflex monitor and automatically calibrated. This minimal invasive device enables calculation of the mean arterial blood pressure (MAP), heart rate (HR), SV and CO using pulse contour analysis of the arterial pressure curve. In addition, it calculates pulse pressure variation (PPV) and stroke volume variation (SVV) as measures of cardiac preload dependency as well as SVR as one of the determinants of left ventricular afterload. Next, a central venous catheter was placed for continuous recording of the central venous pressure (CVP) and the patient was positioned in preparation for surgery. All pressure transducers were located at the level of the right atrium before initiation of the study period. During the subsequent period prior to surgical stimulus, when MAP dropped below 80% of the awake state baseline value for > 3 min, a bolus of phenylephrine 2 µg kg−1 was administered. From 3 min before until 13 min after phenylephrine administration, patient positioning was left unaltered, and no other medication or fluid was administered.No premedication was administered. Upon arrival in the operating theatre, a peripheral intravenous line was inserted and an epidural catheter was placed. After adequate pre-oxygenation, induction and maintenance of anesthesia was pursued by target-controlled total i.v. anesthesia with propofol and remifentanil. At the start of induction of anesthesia, intravenous methylatropine 0.5 mg and epidural levobupivacaine 50 mg were given. After the administration of −1 and pressure for venous return  was calculated as Pvr = Pmsa − CVP.All anesthetic data were collected on the anesthesia monitor  and recorded at 0.2 Hz for subsequent offline analysis. The electronic data were imported into Microsoft Excel 2010®  for analysis. In addition to the recorded variables, an analogue of the mean systemic filling pressure (Pmsa) was calculated using the formula Pmsa = a × CVP + b × MAP + c × CO, in which a = 0.96, b = 0.04 and c is calculated according to anthropometric data . Subsequ−1) was analyzed from 1 min before induction (T−1) of anesthesia until the relative steady state was achieved for all study variables after 10 min (T10). All measurements for the study were performed before surgery commenced.The evolution of the absolute values and of the changes relative to baseline . To detect this difference with an α-error of 0.05 and a power of 0.95, a total of 17 patients is needed [Assuming a normal distribution of the CO data, we considered a mean increase in CO of 15% to be clinically relevant (estimated SD of 0.7 L min0) of 10 mmHg increase in MAP after phenylephrine administration.Normality and homoscedasticity were tested with the Kolmogorov–Smirnov test and modified Levine test, respectively. Continuous data are expressed as mean(SD). For statistical analysis and visualization, the individual patient measurements were synchronized at the moment , and 5(T5) and 10(T10) min afterwards. Results were subject to the general linear model repeated measures ANOVA with Bonferroni adjustment. All statistics were performed using S-PLUS 8.0  and SPSS 23.0 . Significance was set at P < 0.05.The absolute values of the analysed variables were determined at 1 min before the increase in MAP , technical error, or absence of epidural analgesia, atropine, phenylephrine need Fig. . A total−1 at T−1 to 4.94(1.2) L min−1 at T5. Figure The average(SD) CO increased from 3.92(0.87) L min−1 and T5, MAP, SV, CO, CVP and EtCO2 increased by 62, 28, 26, 33 and 11%, respectively, while both dynamic preload variables decreased: PPV dropped from 20% at T−1 to 9% at T5 and to 13% at T10 and SVV from 19 to 11 and 14%, respectively. Between T−1 and T5, the Pmsa increased by 37% and the Pvr by 41%. In addition, while the SVR increased by 37%, the RVR increased by 6% only.Changes in hemodynamics are summarized in Table Phenylephrine is conventionally thought to negatively affect CO, or at best to have no influence if the cardiac contractility is able to overcome the increased afterload without loss of SV . Our hyp1, CVP, PPV, CO, and EtCO2.The main finding of this prospective study was that in patients with anesthesia-induced hypotension and preload dependency—defined as PPV > 12%, phenylephrine increases CO by virtue of an increase in return function. This is reflected in multiple distinct indices, all indicating an increase in CO, owing to a rightward shift in the position of the heart on the Frank–Starling relationship: the dissociation of MAP and SVR at TIn patients undergoing sigmoidectomy, a relative hypovolemia is common owing to the combination of several factors: the patients have been fasting from the night before, had bowel preparation, and received an epidural loading dose, combined with general anesthesia, all causing vasodilation.This pharmacologically induced vasoplegia, together with gravitational venous pooling in the lower limbs due to the leg-down patient positioning—to prevent conflict with the surgeon’s arms—and an increase in abdominal pressure often results in a markedly decreased venous return . While aImportantly, this relative hypovolemic state is just of temporary occurrence. When surgery ends, and the patient awakens, the venous tonus and consequently CO will increase again spontaneously. As such, an alternative to enhance venous return, other than the irrevocable administration of fluids would be desirable. In those cases, the option of recruiting internal blood volume by increasing venous return through reversible pharmacological means such as vasopressors acting predominantly on capacitance vessels might be a potential alternative.In an animal study, the average effect of phenylephrine on CO was related to the preload dependency of the heart: when the heart was preload dependent, phenylephrine induced an increase in CO . SimilarIn contrast to most studies analysing the combined effects of phenylephrine , its ben10, the SVR is not significantly higher compared to T−1, while MAP and CO are still 24 and 20% higher, respectively  CO—which depletes blood from the venous side—there is a persistent increase in CVP, implying that a higher cardiac preload is the primary driving force of the increased CO. This is also reflected in the steep increase in SV from 55 to 70 mL between T2—measured by absorption spectrometry—indicates an increase in CO following phenylephrine [2 from 38(4) to 42(5) mmHg during stable ventilatory settings and invariant HR also indicates an increase in CO owing to increased cardiac preload.As a separate independent measure, the evolution of the EtCOlephrine , 18. TheAn important pharmacological consideration is the rather long biological half-life of phenylephrine of 2–3 h. While clinical experience based on the evolution of the MAP following phenylephrine administration gives the impression of a very short half-life, the fast decline of the MAP after the initial increase merely reflects the redistribution of the phenylephrine, but not its elimination. The long biological half-life of phenylephrine permits to reach a clinically significant plasma concentration in the capacitance vessels. While norepinephrine also has a potent α-mimetic effect, it has a biological half-life of only 2–6 min , 20. BecThis emphasizes the physiological complexity determining the ultimate effect of the used vasopressor on the CO: (1) the balance of α- and β-adrenoceptor effects, (2) the pharmacokinetic properties of the vasoactive molecule, and (3) the preload dependency of the patient.Our study has several limitations: firstly, no echocardiographic measurements of diastolic right and left volumes were performed to assess the preload effects of phenylephrine. The used ProAQT/Pulsioflex device is yet to be formally validated as sufficiently accurate to measure the absolute values of the variables of interest. Although calibrated devices offer more accurate absolute values, the relative changes to baseline values can be acceptably described by pulse wave contour analysis technology for assessing trend changes within a moderate range of acceptable physiological values. Additionally, the accuracy of the calculated SV based on wave-contour analysis may have been affected by the change in arterial elastance following phenylephrine administration . The evoWith respect to the described limitations, the current results must be interpreted within the constraints of potential shortcomings. Neither preload, contractility nor afterload were directly measured by the pulse contour technology. While the observed results suggest an improvement of venous return by virtue of phenylephrine administration, further research relying on direct measurements, like echography or thermodilution will be needed to fully describe the changes in cardiac preload, contractility and afterload in these clinical conditions.In this study, the evolution of the hemodynamic variables was investigated after injection of a single dose of phenylephrine. This strategy was selected in order to most reliably depict the chronology of the hemodynamic changes. Additional research investigating the hemodynamic effects of phenylephrine in different baseline preload states may further elucidate the preload-dependency of these compound effects. The effects during continuous infusion on the investigated variables will have to be precisely determined, as well as comparison with the effects of alternative vasopressors. Ideally, an independent measure of CO, such as ultrasound or thermodilution should have been used to confirm the observed evolution of waveform-derived variables.The prospect to optimize cardiac preload with considerably less fluid administration offers significant clinical advantages but adds complexity due to differences in pharmacokinetics and patient characteristics. Excessive administration of vasopressors may jeopardize organ perfusion, which underlines the importance of advanced hemodynamic monitoring to assess the evolution of the hemodynamic variables for the guidance of the hemodynamic management. In summary, in preload-dependent patients with low SVR, vasopressors could be preferable, while in preload-dependent patients with high SVR, volume administration would be a better choice. Meticulous trend assessment of different indices of CO, volume responsiveness and SVR is imperative to individualize the optimal drug dose to maximise centralisation of blood while avoiding harmful effects on cardiac afterload and organ perfusion.2, in addition to the derived variables SV, SVV, Pmsa, Pvr and RVR.This study indicates that in preload-dependent patients, phenylephrine increases the CO by virtue of an increase in cardiac filling. This is manifested by several distinct hemodynamic indices of CO and venous return, namely the dissociation of MAP and SVR, CVP, PPV, CO, and EtCO


Advanced glycation end products (AGEs) accumulation, a measure of cumulative metabolic stress, constitute a novel pathogenic mechanism involved in aging, diabetes, cardiovascular (CVD) and chronic kidney disease (CKD). Despite removal of uremic toxins and AGEs after a successful renal transplant (RT), CVD remains the leading cause of mortality. We hypothesized that AGEs measurement by Skin Autofluorescence (SAF) might be useful even after a successful RT and thus reflect the high cardiovascular risk burden of these patients.189 stable RT , CKD stages 1–4 and >12 months since RT were enrolled. Variables collected comprised comorbid history, medication use, smoking habit, routine biochemistry, subclinical atheromatosis by ankle-brachial-index (ABI) and allograft resistivity index (RI), 24-h ABPM, anthropometry and handgrip strength. AGEs were measured by SAF and expressed in arbitrary units (AU). Vascular age was estimated by Koetsier´s formula (SAF-0.83/0.024) and expected 10-years cardiovascular death risk was calculated with the REGICOR score.Mean SAF was 3.00±0.83 AU and estimated vascular age 90±34.7 years . SAF was higher among men (3.10±0.91 vs 2.81±0.66), diabetic nephropathy (3.49±0.75 vs 2.96±0.83) and steroid users (3.14±0.86 vs 2.71±0.69). We observed a positive correlation of SAF with night-systolic blood pressure , parathormone , phosphate  and negative with hemoglobin , CKD-EPI , albumin , and dynamometry . Subclinical vascular atheromatosis (ABI and RI) as well as the REGICOR scale (r = 0.35 p<0.001) were also correlated with SAF. In multivariable analysis age, gender, steroid use, serum phosphate and handgrip strength remained independently associated with SAF.SAF levels are elevated in RT patients and correlate with CVD risk. Besides age and male sex, our results suggest that phosphate overload, steroid use and nutritional status are important factors linking to AGEs accumulation. Advanced glycation end products (AGEs) are a variety of compounds produced by the nonenzymatic Maillard reaction that binds reducing sugars with the free amino groups in proteins, lipids or nucleic acids . AGEs caLevels of plasma or urine AGEs have been linked with the severity and prognosis of diabetes, renal and CVD. However, these samples frequently fail to reproduce tissue levels, which more precisely reflect long-standing negative interactions of AGEs , 9. WherIn CKD, accumulation of AGEs is attributed to impaired renal clearance, increased endogenous formation and excess dietary intake , 18. RenTherefore, we hypothesized that AGEs measurement by Skin Autofluorescence might be useful to screen cardiovascular risk even after long-term successful renal grafting. For this aim, we assess SAF in stable RT, with well-characterized clinical and biochemical parameters, in order to investigate factors linked with tissue accumulation of AGEs and analyze its potential significance as a marker of recipient’s cardiovascular risk.2 were also excluded. Immunosuppressive therapy generally consisted of prednisone with a calcineurin inhibitor (mainly tacrolimus) or m-TOR inhibitor, combined with mycophenolate.A total of 189 stable renal transplant patients followed at the nephrology outpatient clinic  were asked to participate in this observational cross-sectional study and written informed consent was obtained from all subjects. Recruitment was performed between May 2016 to June 2017. All procedures were in accordance with the ethical standards for research involving human subjects in the Helsinki Declaration and were approved by the local ethics committee . Only Caucasian patients with stable renal function for the previous three months were included. Subjects under 18 years old, pregnant women, those with acute inflammatory or infectious disease, or those hospitalized in the previous 3 months were excluded. Patients with a double kidney-pancreas graft, type 1 diabetes mellitus or those with uncontrolled malignancy on chemotherapy were not included. As AGEs levels may improve after a renal graft, only those patients followed for more than 12 months after transplantation were screened. To minimize confounding that would be introduced by poor allograft function; participants with estimated glomerular filtration rate (eGFR) of less than 15 mL/min per 1.73 m2, guarded against surrounding light, with an excitation light source between 300 and 420 nm (peak excitation approximately 370 nm). Only light from the skin is measured with a spectrometer in the 300–600 nm range, using a 200 mm glass fiber. SAF is calculated as the ratio between the emission light and reflected excitation light, multiplied by 100 and expressed in arbitrary units (AU). Reproducibility of the device has been tested in different study populations and showed a mean relative error in skin AF of ∼5%  where Vmax is the peak of systolic velocity and Vmin the minimal diastolic velocity. Results are expressed as the average of all these measures. A pathologic RI was defined as a value ≥ 0.8. Blood pressure was monitored by 24 h-ambulatory blood pressure monitoring (24h-ABPM). Concomitant medications including antihypertensive treatment, immunosuppression (IS) and statins were also recorded.The REGICOR (REgistre GIroní del COR) formula was used to estimate the 10-year risk of mortality from cardiac disease. This is a modified Framingham Risk Equation based on age, gender, systolic and diastolic blood pressure, smoking status, diabetes, total cholesterol and high-density lipoprotein cholesterol that has been validated for the Spanish population .2) and handgrip muscle strength measured in the non-dominant arm using the Baseline Hydraulic Hand Dynamometer .Anthropometric measurements, including mid-upper arm circumference (MUAC), height, waist and weight were performed during the clinical examination. Body mass index (BMI) was calculated (kg/m2 was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) [Blood and urine laboratory measurements  included serum creatinine, uric acid, proteinuria , bicarbonate, calcium, phosphate, parathyroid hormone (PTH), vitamin D, C-reactive protein, ferritin, hemoglobin, glycated hemoglobin (HbA1c) and lipid profile. Albumin and transferrin concentrations were used as biochemical markers of nutritional status. All measurements were part of our routine patient visits and analyzed centrally at the hospital laboratory. eGFR expressed as mL/min per 1.73mCKD-EPI) . PhosphaU-test. All results were expressed as means and standard deviation unless otherwise stated. Pearson´s or Spearman´s correlation coefficient, as appropriate, was used to evaluate bivariate relationships between continuous variables. The χ2 test or Fisher exact test, if applicable, were used to compare categorical variables by cross tabulation. Multivariate linear regression analysis using the stepwise backward-selection method was also performed to identify the independent predictors of SAF (measured as a continuous variable) after adjusting for the significant univariate variables. Unadjusted P-values less than 0.05 were considered significant.Statistical analyses were performed using SPSS version 21 . The primary goal was to evaluate SAF (AU) relationship with clinical, biochemical, nutritional and surrogate CVD markers. Normal distribution of the variables was evaluated using the Kolmogorov-Smirnov test. Accordingly, both parametric and non-parametric tests were used as appropriate. Differences in continuous variables for important selected strata were tested using the t-student or Mann-Whitney Results, for the total 189 enrolled patients , are presented in 2. According to CKD stages (KDOQI classification), 5 patients (3%) were on stage 1, 50 (26%) on stage 2, 101 (53%) on stage 3 and 33 (18%) on stage 4. Whereas microalbuminuria was present in 44% of cases, 16% showed overt proteinuria. Nutritional parameters, namely mean BMI and handgrip strength, were 28.9 ± 5.45 kg/m2 and 30 ± 10.4 Kg respectively.Graft function estimated by the CKD-EPI was 49.6 ± 20.01 ml/min/1.73 mMean skin autofluorescence was 3.00 ± 0.83 (1.5–6.4) AU. Estimated vascular age for the whole group was 90 ± 34.7 years . Comparison of potentially relevant categorical variables  are showed in Univariate correlates of SAF are displayed in SAF was associated with atherosclerosis damage estimated by ABI (r = -0.17) and intragraft resistivity index (r = 0.18). Of note, as shown in Stepwise linear regression analysis was performed to determine the parameters that independently associated to SAF. In a final model which explained 53% of the variance of skin-AF, age, male gender, steroids use, serum phosphate and handgrip strength emerged as independent contributors, as shown in SAF is a marker of AGEs accumulation and predictor of CVD mortality in aging, diabetes mellitus and CKD –16. We pWe also found an association between SAF intensity and male sex that has not been consistently seen in previous studies also carried out after RT , 22. HowGlycation adducts in tobacco and smoke can form cross-links with proteins . Despitemilieu of dyslipemia, insulin resistance and reduced antioxidant defenses. Collectively, this may enhance both lipid and protein glycosylation contributing to elevated SAF values [As expected, we have found a relation with diabetic nephropathy but it did not stand multivariable adjustment. Moreover, postransplant diabetes was also not statistically associated with SAF. Diabetes might be a sufficient condition but it is not essential for AGE cardiovascular damage . We specF values , 33, 34.Interestingly, a novel finding in our study was the independent association between use of steroids and SAF intensity, something that would need confirmation in subsequent studies. The wide range of post-transplant period (12–468 months) that may include different immunosuppressive protocols  and the cross-sectional design of the study (comparing patients with and without steroids at that moment), may interfere with this observation. Moreover, as only patients from a single center were enrolled, these results are not to be generalized without further considerations.It has been proposed that in the presence of certain risk factors, circulating AGEs may deposit in blood vessels including graft microvasculature and tubular cells, contributing to renal function decline ,35. In cIn contrast to other studies ,22, we dUremic mineral-metabolism disturbances (CKD-MBD) are largely restored after successful renal transplantation. For instance, fibroblast growth factor (FGF-23) returns to normal values one year after RT though hyperparatiroidism and relatively low phosphate levels may persist in the long-term . HoweverBeyond phosphate influence, AGEs deposit in the vessel wall and atherosclerotic plaques have been postulated to contribute to the progression of CVD in diabetes or CKD and to associate with the risk of mortality , 45, 46.As hypothesized, skin AF may represent a clinically useful, non-invasive method, to assess cardiovascular risk in RT. Limitations of our analysis are, however, its cross-sectional nature that precludes any causation in the associations observed, and the lack of circulating or direct tissue AGEs assessment. Besides age and male gender, our results indicate that serum phosphate, steroid use and nutritional status are the major determinants of SAF after long-term RT. If AGE deposition is the corner stone linking PEW, glucocorticoids and CVD after RT as well as their role as a new therapeutic target requires further prospective investigations.


Ischemic stroke is a common neurologic condition and can lead to significant long term disability and death. Observational studies have demonstrated worse outcomes in patients presenting with the extremes of blood pressure as well as with hemodynamic variability. Despite these associations, optimal hemodynamic management in the immediate period of ischemic stroke remains an unresolved issue, particularly in the modern era of revascularization therapies. While guidelines exist for BP thresholds during and after thrombolytic therapy, there is substantially less data to guide management during mechanical thrombectomy. Ideal blood pressure targets after attempted recanalization depend both on the degree of reperfusion achieved as well as the extent of infarction present. Following complete reperfusion, lower blood pressure targets may be warranted to prevent reperfusion injury and promote penumbra recovery however prospective clinical trials addressing this issue are warranted. Stroke is a common neurologic emergency worldwide with an overall growing incidence particularly in low to middle income countries where there has been over a 100% increase in stroke events over the past four decades , 3. IV tIn order to understand the principles of blood pressure management during AIS revascularization, it is useful to review fundamental aspects of blood flow in cerebral ischemia and infarction. Following complete cessation of cerebral blood flow (CBF) there is loss of normal neuronal electrical activity within seconds due to energy failure, disruption of ion homeostasis and membrane depolarization , 18. If Early clinical studies using carotid clamping revealed that the risk of transitioning from ischemic to infarcted tissue depends on both the magnitude and duration of hypoperfusion . FurtherIn the healthy brain, CBF is tightly regulated to meet regional metabolic demand and this is accomplished through the process of cerebral autoregulation whereby resistance-level blood vessels constrict or dilate across a range of systemic pressures  in order to maintain a more constant flow . When prWhile reestablishing CBF is essential for survival of ischemic tissue, reperfusion itself can contribute to significant neurologic injury in the form of infarction, edema and hemorrhagic transformation , 35. RepElevated BP is common in patients presenting with AIS, with one study involving more than 250,000 patients demonstrating a systolic blood pressure (SBP) > 140 mmHg in approximately three-fourths of patients . Severe In several cohorts, a U-shaped relationship exists between BP and outcome in AIS in which both extremes of BP have prognostic significance for death and disability. In a retrospective analysis of the International Stroke Trial, patients presenting with SBP 140–179 mmHg had the lowest likelihood of death or dependency at 6 months with a nadir at around 150 mmHg . For eveIn clinical studies, dynamic fluctuations in BP have been identified as a strong prognostic marker in AIS and increase the risk of intracranial hemorrhage following IV t-PA . BP variIn the 2018 guidelines for management of AIS from the American Heart Association (AHA), BP may be permitted up to 220/120 mmHg in patients presenting with AIS who are not candidates for either IV t-PA or IAT and do not have another contraindication to an elevated BP . In patiThe overall approach to AIS treatment is multifaceted and relies upon optimized systems of care to identify, triage and treat patients presenting with acute neurologic symptoms with the goal of reestablishing cerebral perfusion and minimizing secondary injury. In order to appreciate aspects of hemodynamic management in AIS, it is constructive to separate it into stages of treatment beginning with the initial assessment, during revascularization, and post-intervention see . Each stHypertension is very common in AIS with 21–50% of patients presenting with blood pressure higher than the threshold eligible to receive IV t-PA , 42, 49.For patients who are candidates for IAT there is considerably less data to guide management of initial blood pressure. However, several insights are apparent through retrospective analyses. In the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial, patients presenting with SBP > 150 mmHg were less likely to achieve recanalization compared to those with lower pressures despite similar thrombus characteristics . Since hAnother important aspect to consider when evaluating AIS patients in the initial setting is intravascular volume status. In several observational studies, up to half of patients presenting with AIS are dehydrated (defined as an elevated BUN to creatinine ratio) and this has been correlated with increased in-hospital mortality and placement in institutional care at discharge , 61. PatFor patients undergoing IAT, predictors of poor outcome include higher National Institutes of Health Stroke Scale (NIHSS) score, lower Alberta Stroke Program Early CT Score (ASPECTS), carotid terminus occlusion, and failed recanalization , 66. As With the emergence of IAT as a prominent treatment for patients presenting with LVO, multiple questions have arisen regarding optimal treatment practices including whether general anesthesia (GA) or conscious sedation (CS) is preferable for patients undergoing thrombectomy. CS offers the advantages of allowing for neurologic assessment throughout the procedure and eliminating delays associated with anesthesia induction. GA on the other hand may reduce the risk of aspiration and eliminates patient movement thereby potentially making the procedure safer and more technically feasible . Early oWhile these studies seem to provide compelling evidence that CS is preferred over GA, several important methodologic issues must be addressed. First, these were all retrospective studies and possess significant selection bias as patients treated with GA were more likely to have higher NIHSS scores, lower ASPECTS, and were more likely to have carotid terminus and vertebrobasilar occlusions as well as premorbid coronary heart disease , 72–75. Recently three randomized controlled clinical trials have been published comparing the impact of CS to GA in patients treated with IAT. In contrast to prior retrospective analyses, patients treated using CS did not have better outcomes compared to those who underwent GA and in both the Sedation vs. Intubation for Endovascular Stroke Treatment (SIESTA) and General or Local Anesthesia in Intra-arterial Therapy (GOLIATH) trials, GA was associated with higher rates of functional independence at 3-months –80. WhilThe AHA ischemic stroke guidelines recommend maintaining a BP < 180/105 mmHg for at least 24 h in patients treated with either IV t-PA or IAT to promote perfusion to ischemic territories while mitigating potential risks of intracranial hemorrhage , 53. In After successful recanalization, there is often a significant spontaneous decline in BP over 12–24 h compared to patients with persistent occlusion , 85. ForThough randomized trials of BP control following IAT are lacking, Goyal et al. published a single center's experience with different BP targets following IAT over 4 years. Following good reperfusion, patients were either assigned to permissive , moderate (<160/90 mmHg) or intensive (<140/90 mmHg) BP targets in a non-randomized fashion . While pVarious agents are routinely used to manage hypertension in stroke however clinical trials utilizing BP agents in AIS have been inconclusive with some reports of marginal or no benefit while others suggest a risk of more severe disability in treated patients. Studies using angiotensin-converting enzyme (ACE) inhibitors or calcium channel blockers within the acute hypertensive phase of AIS have demonstrated significant acute reductions in blood pressure however this was not accompanied by changes in death or disability at 14 or 90 days –96. MoreLabetalol is a mixed α and β adrenergic blocker often used to control blood pressure post-AIS. Though it has less β-1 activity compared to other beta blockers, labetalol can exert negative chronotropic effects thereby limiting its utility in patients with significant bradycardia . HoweverAs a dihydropyridine calcium channel blocker, nicardipine is more selective for vascular rather than myocardial calcium channels and generally exerts a neutral effect on heart rate . When coClevidipine is a newer dihydropyridine calcium channel blocker which is also included as a treatment modality in the AHA 2018 guidelines . SimilarHydralazine is a direct acting vasodilator that is often used for hypertensive emergencies . DespiteEnalaprilat, the active metabolite of enalapril, is an intravenous angiotensin-converting enzyme (ACE) inhibitor which can lower BP without impacting cardiac chronotropy . AdditioSodium nitroprusside is a potent venous and arterial vasodilator often used as an infusion in hypertensive emergency . HoweverGlyceryl trinitrate, or nitroglycerin, is a nitric oxide donor that primarily causes venodilation, as well as arterial dilation at high doses, thereby effectively reducing preload and BP . GlyceryUrapidil is an antihypertensive agent available throughout Europe and Asia and recommended by the European Stroke Initiative (EUSI) though it is not currently approved by the United States Food and Drug Association (FDA). Urapidil is a unique antihypertensive agent which exerts peripheral vasodilation through alpha-1-adrenoreceptor antagonism as well as sympatholytic effects via serotonin 5HT1A receptor stimulation . Animal In animal models of AIS, induced hypertension (IH) improves CBF to the ischemic territory and reduces final infarct volume compared to normotensive controls , 122. PhHemodynamic management in AIS is an involved and complex process that aims to balance the competing interests of supporting CBF to the ischemic penumbra while avoiding reperfusion injury. Decades of observational studies have demonstrated a U-shaped association between BP and stroke outcomes. However, studies aimed at controlling hemodynamics have been inconclusive. In the setting of thrombolytic therapy, the pendulum may shift from a higher risk of hypoperfusion to that of reperfusion injury, therefore making BP control particularly paramount. This is especially relevant in IAT where rates of LVO recanalization are substantially higher than in other treatment modalities and revascularized patients could benefit from lower BP thresholds to prevent intracranial hemorrhage and cerebral edema. Well-designed prospective multicenter controlled clinical trials are now warranted to better understand the relationship between various BP goals during and post-embolectomy with particular focus on interactions with recanalization status. In the meantime, careful monitoring and management of hemodynamics is essential for prevention of significant hypo- or hypertension as well as minimizing BP variability in order to best promote tissue recovery while preventing secondary injury.JH and JV manuscript concept and design. JV initial manuscript draft. MT and JH critical review of manuscript and addition of sections. All authors reviewed, edited, and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.