This is the first study focusing on perioperative blood glycemic monitoring for the incidence of surgical site infection (SSI) among patients with type II DM (T2DM) during the 1-year follow-up after emergent orthopedic surgery. We retrospectively collected the data of 604 patients who had received surgery for unilateral lower limb traumatic fracture from January 2011 to January 2021, including 215 men and 389 women with a mean age of 71.21 and a mean BMI of 25.26. In total, 84 (13.9%) of them developed SSI during the 1-year follow-up. Higher preoperative and postoperative -3-month hemoglobin A1c (HbA1c) and AC blood glucose and the presence of rheumatoid arthritis were all associated with increased rates of SSI. The thresholds for predicting SSI were the following: (1) preoperative HbA1c > 7.850% (area under curve [AUC] = 0.793); (2) postoperative HbA1c > 6.650% (AUC = 0.648); (3) preoperative AC blood glucose > 130.50 mg/dL (AUC = 0.773); and (4) postoperative AC blood glucose > 148.5 mg/dL (AUC = 0.709) by receiver-operating characteristic curve method. These findings may provide a useful control guideline for patients with T2DM older than 50 years old and who received surgery for a lower limb fracture in the prevention of postoperative SSI. The international diabetes federation reports that approximately 536.6 million (about 10.5% of the world population) adults had diabetes mellitus (DM) worldwide in 2021; this figure is expected to rise to 783.2 million 12.2%) by 2045 , and no .2% by 20The ethics committee of the Institutional Review Board of the Buddhist Tzu Chi Medical Foundation Hualien Tzu Chi Hospital approved the study’s retrospective protocol (IRB 111-016-B). The study protocol was implemented in accordance with the Declaration of Helsinki. We conducted a retrospective, observational single-center study from January 2011 to January 2021. Patients were included if they (1) were aged 50 years or older, (2) had T2DM, (3) had received surgery for unilateral lower limb traumatic fracture within 2 weeks of trauma, (3) had available data of their preoperative blood hemoglobin A1c (HbA1c) and AC glucose levels, and (4) had available data of their postoperative 3 months blood hemoglobin A1c (HbA1c) and AC glucose levels. Data on the patients’ demographic characteristics, including age, sex, BMI, and medical comorbidities, were also collected. Data on medical comorbidities, including hypertension, dyslipidemia, coronary artery disease (CAD), cerebral vascular accident, hepatic disease, chronic renal failure (CRF), and rheumatoid arthritis (RA), were analyzed. We excluded the patients who (1) had open fractures, (2) had medical conditions that delayed the surgery for fracture for more than 2 weeks after trauma, (3) had missing data or loss of follow-up 1-year post-trauma, and (4) had haemoglobinopathies such as thalassemia. The outcome was the incidence of surgical site infection (SSI) during 1 year postoperative. SSI was defined as (1) superficial SSI if any one of the following criteria were met: only infiltrates the local skin or subcutaneous tissue or involves an inpatient who needed antibiotic treatment for wound problems, including redness, swelling, heat, or pain, regardless of any microbiology results; (2) deep SSI if any one of the following criteria were met: deep fascia infection, local site abscess needing surgical debridement, persistent effusion or dehiscence of the wound, or the necessity of the implant removal or revision for infection control. These patients’ wound exudates were sent for causative agent culture and sensitivity .t-test were used to compare the men’s and women’s demographic characteristics. Multiple logistic regression was performed to determine the independent predictors for postoperative 1-year SSI. We used these models to identify the correlation of preoperative and postoperative HbA1c/AC glucose levels with postoperative SSI. A receiver-operating characteristic (ROC) curve was plotted to assess the diagnostic performance of preoperative and postoperative (3-month) HbA1c and AC glucose in SSI prediction. Sensitivity, specificity, and the area under the curve (AUC) were calculated, and we determined the optimal thresholds that indicate SSI, recurring to the Youden index. A two-sided p value < 0.05 indicated statistical significance.SPSS for Windows  was used for statistical analyses. Categorical variables are presented in terms of the frequency and proportion, and continuous variables are presented in terms of the mean ± standard deviation. A Chi-square test and an independent The patients’ demographic characteristics are shown in Specifically, the sample comprised 604 patients with more women than men (64%), a mean age of 71.21, a mean BMI of 25.26, a mean preop HbA1c of 7.55, and a mean preop blood glucose level of 146.83. In total, 50 of them (8.3%) were newly diagnosed T2DM. The comorbidities included hypertension (82%), dyslipidemia (44.2%), CAD (31.5%), cerebrovascular accident (27%), hepatic disease (18.4%), CRF (31%), and RA (39.2%). Among the 604 patients, 84 (13.9%) developed SSI. There were 62 superficial SSI and 22 deep SSI. The range of the occurrence of superficial SSI from the date of surgery was from 2 to 74 days, while that of deep SSI was from 11 to 110 days. The most frequent cultured pathogens were Staphylococcus aureus and Pseudomonas aeruginosa, as shown in Four adjusted models were constructed to evaluate the independent effect of the four glycemic indicators on SSI. Models 1 to 4 included preoperative HbA1c, postoperative HbA1c, preoperative blood glucose, and postoperative blood glucose, respectively. Our results are summarized in p < 0.001), postoperative HbA1c OR of 1.43 , preoperative blood glucose OR of 1.02 , and postoperative blood glucose of 1.01 . Hypertension was associated with decreased rates of SSI in model 1  and model 2 . Age was associated with decreased rates of SSI in model 3  and model 4 . In model 3, CAD was associated with increased rates of SSI , whereas cerebrovascular accident was associated with decreased rates . Notably, comorbidity with RA was associated with increased rates of SSI in all four models, with an OR of 2.5 (95% CI: 1.39–4.48 p = 0.002) in model 1, an OR of 2.53 (95% CI: 1.48–4.33 p = 0.001) in model 2, an OR of 2.97 (95% CI: 1.48–5.99 p = 0.002) in model 3, and an OR of 2.85 (95% CI:1.55–5.23 p = 0.001) in model 4.All four glycemic indicators were associated with increased rates of SSI in their adjusted models, with a preoperative HbA1c odds ratio (OR) of 1.77 , the best threshold, and the corresponding sensitivity and specificity for all four glycemic indicators on SSI. The AUROC results indicated that preoperative HbA1c  A, preopeThis study indicated that increased perioperative blood glucose and HbA1c are associated with higher SSI rates. We also provided thresholds for each glycemic index, with high to moderate predictability confirmed by AUROC. Additionally, we showed that patients are at greater risk of SSI if previously diagnosed with RA. Consistent with similar research ,7,16,19,Blankush et al. (2016) demonstrated that a preoperative HbA1c level may not be independently associated with the risk of postoperative infection in 2200 patients undergoing nonemergent procedures, but it may be useful for predicting an increased risk of infectious complications for subgroup analysis . Werner Additionally, our study showed that, among all comorbidities, RA is the only factor significantly associated with SSI in all models; that may be due to the disease itself, associated commodities, or the use of immunosuppressive medication . Our finThis study had several limitations. First, the number of cases in our 10-year period was relatively small because many emergent-surgery patients did not have adequate monitoring data on HbA1C or AC glucose for follow-up. Second, this study did not include the patients’ DM medication, lifestyle, or dietary habits, which may influence their blood glycemic control quality. Third, we did not do further subgroup analysis for the different surgical methods for different kinds of lower limb fractures. Despite these limitations, this study provides the prediction thresholds that have good discrimination quality for preoperative and postoperative (3-month) HbA1c and AC glucose; these thresholds can be used as a reference for perioperative DM control and infection control precaution in preventing postoperative SSI among middle-aged and older adult patients. This is the first study focusing on perioperative blood glycemic monitoring for emergent lower limb fracture surgery. Further long-term follow-up on the influence of the control of T2DM parameters on the incidence of postoperative complications of limb fractures among large cohort groups will be our future research.We demonstrated that higher preoperative and postoperative blood glucose and HbA1c and RA are associated with a higher risk of SSI for T2DM orthopedic trauma patients. The threshold for predicting SSI were (1) preoperative HbA1c > 7.850%; (2) postoperative HbA1c > 6.650%; (3) preoperative blood glucose > 130.50 mg/dL; and (4) postoperative blood glucose > 148.5 mg/dL. These glycemic index thresholds obtained from ROC have high to moderate predictive performance for postoperative 1-year SSI, and preoperative HbA1c seemed to be the best predictive value for SSI.


Correction to: Clinical Rheumatologyhttps://doi.org/10.1007/s10067-022-06263-3The original published version of the above article contained incorrect Key Points. The authors requested to note the following corrected points.The Key Points of the article should be:Key Points:1. HPLC-MS identified increased serum Kyn/Trp ratio in DM patients, which positively correlated with levels of muscle enzymes and inflammatory markers and was downregulated upon treatment.2. Cox regression analyses identified ln(Kyn/Trp) as an independent prognostic predictor of mortality in DM.3. Monitoring intrinsic immune regulation function should be considered a potential therapeutic target in DM patients.Instead of:Key Points:1. HPLC–MS identified increased serum Kyn/Trp ratio in DM patients, which positively correlated with levels of muscle enzymes and inflammatory markers and was downregulated upon treatment.2. More attention to psychological status is needed in RA patients.3. Cox regression analyses identified ln(Kyn/Trp) as an independent prognostic predictor of mortality in DM.The original article has been corrected.


A higher drop in diastolic blood pressure (DBP) was even independently associated with a poor 90-day outcome (p = 0.024). Conclusion: A GA-related drop in DBP may independently predict a poor long-term outcome in stroke patients undergoing thrombectomy.Background: Several factors affect the efficacy of endovascular thrombectomy (EVT); however, the anesthesia-related factors have not been fully explored. We aimed to identify independent predictors of outcome by analyzing procedural factors based on a multicentric stroke registry. Methods: Data of consecutive patients with acute ischemic stroke (AIS) were extracted from the prospective STAY ALIVE stroke registry. Demographic, clinical, and periprocedural factors including hemodynamic values were analyzed in patients undergoing thrombectomy with either general anesthesia (GA) or conscious sedation (CS). Independent predictors of outcome both at 30 and 90 days based on the modified Rankin Scale (mRS: 0–2 as favorable outcome) were also explored. Results: A total of 199 patients (GA: 76 (38%) vs. CS: 117 (59%); in addition, six patients were converted from CS to GA) were included. The minimum value of systolic, diastolic, and mean arterial pressure was significantly lower in the GA compared to the CS group, and GA was associated with a longer onset to EVT time and a higher drop in all hemodynamic variables (all,  Although the efficacy of mechanical thrombectomy in patients with acute ischemic stroke (AIS) has been proven in multiple studies—see Refs. ,5,6,7,8—An elevated blood pressure level in patients with AIS is common in the emergency phase, suggesting that the collateral perfusion to the penumbra is blood pressure-dependent. However, in the pre-endovascular thrombectomy era, several studies that reported greater values for SBP at the time of stroke presentation were associated with less favorable outcomes . In the Instead of using a one-size-fits-all approach, we assumed that an individual approach to blood pressure management would be preferable. An individualized approach may facilitate the avoidance of serious complications such as hemorrhagic transformation or expansion of infarct volume. Whereas the guideline clearly states avoiding hypotension and hypoperfusion in the acute phase of ischemic stroke, there is no recommended cut-off value for blood pressure components . Thus, tThe study protocol was approved by the Local Ethics Committee at the University of Pécs Medical School and informed consent was obtained from each patient according to the “Good Clinical Practice” (GCP) guidelines (35403-2/2017/EKU) .2. Patients outside this area were also admitted on a case-by-case basis. Stroke was defined according to the World Health Organization [Enrollment in this study was based on a protocol previously published by our research team: the STAY ALIVE Acute Stroke Registry, which is a prospective, ongoing multicenter registry, was designed to build a complete information system for the management of acute ischemic stroke care in the Southern Transdanubian Region, Hungary. Based on census data from 2011, the estimated population of the study area was approximately 1.103.000 inhabitants who lived in area of 16.576 kmnization . All patnization . All ASPnization .We retrospectively reviewed our prospectively collected cohort for consecutive patients with AIS who received EVT. However, due to the limited accessibility of anesthesia records, only patients treated in the clinical center of Pécs were included in the statistical analysis.Patients with AIS undergoing an EVT between October 2017 and July 2019 were divided into 2 groups, depending on the type of anesthesia used during the procedure, which was chosen at the discretion of the treating anesthesiologist: patients receiving general anesthesia (GA group) or patients receiving conscious sedation (CS group). Patients converted intraoperatively from CS to GA were considered as part of the GA group. All patients were monitored and managed by anesthesiologists throughout the whole procedure. Propofol (1.5–2.5 mg/kg) was exclusively used as an induction agent, combined with fentanyl and followed by sevoflurane (target: about 1.0 MAC) as maintenance in the GA group. CS included the use of either propofol or midazolam or nalbuphin in a sedative dosage as constant infusion or intravenous bolus at the anesthesiologists discretion. Depth of anesthesia was not monitored by BIS.GA included induction with propofol, fentanyl, and atracurium, followed by endotracheal intubation and subsequent controlled mechanical ventilation. CS included the use of either propofol, midazolam, or nalbuphin in a sedative dosage as constant infusion or intravenous bolus at the anesthesiologist’s discretion. Furthermore, fentanyl was used in most cases as an analgetic.2), and invasive blood pressure via arterial catheter [Patient monitoring consisted of continuous ECG, pulse oximetry, capnography , clinical data , and laboratory parameters  were collected. Outcome data were assessed by trained personnel via telephone follow-up. Outcome measures were determined by modified Rankin scale (mRS) after 30 and 90 days. A favorable outcome was defined as mRS 0–2, and a poor outcome as mRS 3–6.Anesthetic data were collected from the start of anesthesia till the end of the procedure. Extracted data included the type of induction and maintenance, the drugs used, respectively, and hemodynamic values. Blood pressure was measured either non-invasively or invasively. In the case of invasive measurement, these values were preferably used since they are more accurate and readily available.Hemodynamic values were manually recorded in the anesthetic report every 5 min and manually evaluated. Maximal systolic blood pressure (SBPmax) was defined as the highest periprocedural systolic blood pressure, and minimal systolic blood pressure (SBPmin) as the lowest periprocedural systolic pressure. The systolic blood pressure difference (SBPdiff) was calculated based on the difference between SBPmax and SBPmin. The diastolic blood pressure parameters , minimal diastolic blood pressure (DBPmin), diastolic blood pressure difference (DBPdiff)) were collected and calculated accordingly. Mean arterial pressure (MAP) was calculated as DBP + 1/3 (SBP-DBP), with MAPmax being the highest MAP, MAPmin being the lowest MAP, and MAPdiff being the difference between these two parameters. Pulse pressure was calculated as the difference between the systolic and diastolic blood pressure, with PPmax being the largest difference between SBP and DBP, PPmin being the lowest difference, and PPdiff being the difference between PPmax and PPmin.t test for continuous data were used for analysis of demographic and clinical factors. Nonparametric Mann–Whitney U test was used for non-normally distributed values. Data were presented as median and interquartile range (25th–75th percentiles), as well as mean ± SD. A binary logistic regression was used to predict favorable 30- and 90-day outcome, adjusting for age, sex, NIHSS, type of anesthesia, and hemodynamic values. The ideal cut-off value with the best sensitivity and specificity of hemodynamic parameters was determined based on the area under the curve (AUC) using ROC analysis. Correlation analysis was performed by calculating the Spearman correlation coefficient (rho). A p value < 0.05 was considered statistically significant. In case of missing data, imputation was not used. All anesthetic data mentioned in the “Data Collection and Outcome Measures” section were accounted for.Data were evaluated using the SPSS software package . The Kolmogorov–Smirnov test was applied to check for normality. Chi-square test for categorical data and Student n = 32 vs. 20, p = 0.029 and CS group: 46 vs. 27, p = 0.017).A total of 199 patients were enrolled between October 2017 and July 2019. The mean age was 69 ± 12 years, and 90 patients of the total population were male (45.2%). There was no difference in age and sex distribution in the groups . Preexisp = 0.009), after thrombectomy (7 (IQR 2–12) vs. 10.5 (IQR 5–15); p = 0.008), after 24 and 72 h (6 (IQR: 1–12) vs. 9 (IQR: 5–14), p = 0.003; 5, IQR 0.75–10.25 vs. 8, IQR 4.5–13, p = 0.002) were significantly different. The door to recanalization time was on average 19 min longer in the GA group . There was no difference in hemodynamic parameters on admission . However, significant intra-interventional differences in hemodynamics were observed between both techniques. While the maximal blood pressure values (mmHg) have not shown statistical difference , the minimal values were all significantly higher in the CS group than in the GA group . Comparing the CS vs. GA groups, the difference between maximal and minimal pressure values  was significantly lower in patients treated under conscious sedation , suggesting a favorable intraprocedural hemodynamic state in the CS group.In 76 patients (38.2%), GA was the mode of anesthesia, while six more patients (3.0%) had their intervention started under CS, but were later converted into GA during the procedure. The NIHSS before thrombectomy (CS: 11 (IQR:7–16) vs. GA: 14 (IQR: 11–18); p = 0.05), 5 (p = 0.034); mRS 90 days: 0 (p = 0.019), 4 (p = 0.036), and 6 (p = 0.020).Significant differences in terms of clinical outcome dependent on DPBdiff were found in patients between both groups: mRS 30 days: 0 (p = 0.024).While the only independent predictors of 30-day outcome were age and NIHSS at 24 h post-stroke, the latter remained an independent predictor of the 90-day outcome too. Furthermore, the maximal difference in periprocedural diastolic blood pressure (DBPdiff) was also found to be an independent predictor of such long-term outcome  (OR: 0.9p < 0.001). However, if the same analysis was performed in the GA group, DBPdiff ≥ 32.5 mmHg as a cut-off value predicted a poor 90-day outcome with a sensitivity of 65% and a specificity of 72% .Based on ROC analysis in the total population, the maximal drop of DBP ≥ 27.5 mmHg as a cut-off value predicted a poor 90-day outcome with a sensitivity of 60% and a specificity of 70%  under general anesthesia (GA) or conscious sedation (CS). Analyzing the clinical appearance of the patients undergoing EVT, a lower NIHSS after thrombectomy, at 24 h and at 72 h, could be seen in the CS group. However, their baseline NIHSS prior to thrombectomy was also significantly lower. A possible explanation for these findings could be the significantly longer door to revascularization time in the GA group, which could be observed. Other studies show different results regarding the periprocedural times, such as door to groin puncture time, door to revascularization time, or onset to revascularization time, with some conflicting results  and otheIn the analysis of interventional hemodynamic parameters, the maximal values of systolic and diastolic blood pressure , mean arterial pressure (MAPmax), and pulse pressure (PPmax) showed no significant difference. However, the minimal pressures were significantly lower in the GA group compared to the CS group, as can be explained by the systemic cardiovascular effect of anesthetic agents. Comparable findings have been shared in the past by Melinda, J. et al., even though this comparatively older study had its own limitations . SimonseDespite the differences in the hemodynamic values, the only independent predictors of the short-term outcome were age and post-procedural NIHSS, suggesting that older patients and patients with a higher NIHSS after thrombectomy have a worse clinical outcome after 30 days. Other studies have shown similar predictors of 30-day clinical outcome ,32. ImpoRegarding outcome measurements, there seems to be an association between the type of anesthesia and clinical outcome, with people in the CS group showing a more favorable outcome. As shown, a higher DBP and a lower difference between maximal and minimal periprocedural diastolic pressures might be associated with a favorable clinical outcome. Patients with a larger drop in periprocedural DBP undergoing thrombectomy under GA showed higher mortality than patients under CS. Nevertheless, this should be validated in a larger prospective trial including more anesthesia and neurointervention-related factors  ,34,35,36This study shows, on one hand, the impact in terms of hemodynamic volatility in patients suffering from AIS treated with GA compared with CS. Furthermore, it may suggest an association of hemodynamic values, the DBPdiff specifically, with long-term clinical outcome and mortality.However, this study has several limitations: (i) this is a post-hoc analysis, which means that the results should be further investigated by a randomized control trial with the aim to find differences in hemodynamic values between GA and CS; furthermore, since it is an observational study, there might have been a bias towards using GA patients with initially worse clinical appearance (the baseline NIHSS were higher in the GA group than in the CS group); (ii) this is a single-center analysis of a multi-center registry, resulting in possible treatment bias, since the induction and maintenance was left to the anesthesiologist’s discretion; (iii) only 199 patients were enrolled in this study, with only 76 being in the GA subgroup; further studies, ideally randomized controlled trials, should work with larger and more balanced subgroups; (iv) the presence of missing data may have introduced bias into our study; however, in our most important outcome (mRS after 30 and 90 days), data appear to be missing at random; (v) since the method of blood pressure measurement was not predetermined, some patients had invasive and others non-invasive blood pressure measurement, resulting in possible discrepancies and thus not being exactly comparable; (vi) the baseline NIHSS were higher in the GA group than in the CS group; this might explain the lower postprocedural NIHSS in the CS group; (vii) post-procedural hemodynamic parameters were not monitored as part of this study; however, all recruited patients were monitored and managed in a neurosurgical intensive care unit and post-procedural blood pressure was maintained according to current guidelines.In conclusion, these findings underscore the importance of hemodynamic management during EVT and highlight the need for further investigation of blood pressure management after large-vessel occlusion stroke.


Blood pressure is maintained by a combined mechanism of the baroreceptor reflex and the vestibulosympathetic reflex. This study is intended to verify the hypothesis that the orthostatic hypotension (OH) seen when benign paroxysmal positional vertigo (BPPV) occurred may act as a factor that affects the recurrence of BPPV. The subjects of present study were selected from among 239 patients diagnosed with idiopathic BPPV. The average age of the group with OH was 59.3 years, and the age of the group without OH was 50.3 years, with a statistically significant difference (P = 0.013). It was shown that drug-taking increased the risk of OH occurrence by 4.08 times (C.I for exp(B): 1.20–13.77) compared to the group that did not take drugs. It was shown that the risk of recurrence of BPPV was significantly reduced in the no recurrence group compared to the multiple recurrence group when there was no OH . Also, the risk of recurrence was significantly reduced in the no recurrence group compared to the multiple recurrence group when there was no drug-taking (p = 0.000 aOR 0.0000001). This study is the first study that studied the effect of OH on the recurrence of BPPV and showed the possibility that OH could partially influence the recurrence of BPPV. The symptoms of vertigo can occur when there is an abnormality in any part of the visual system, the vestibular sensory system, and the somatosensory system for body balance, and the central nervous system that integrates the foregoing. Benign paroxysmal positional vertigo (BPPV) is one of the diseases that cause vertigo due to changes in the position of the vestibular sensory system, and the drop out of the otolith in the semicircular canals or excessive movements of the cupula cristae ampullaris is thought to be the cause of BPPV.1.BPPV is also a disease that is prone to recurrence. In general, its recurrence rates within 1 year and 3 years are known to be 17% and 50%, respectively. The causes of recurrence are known to be age, vitamin D deficiency, chronic diseases such as hypertension and diabetes, and otologic diseases2.The vestibular sensory system is known to send signals through the sympathetic nervous system to the nucleus tractus solitarius (NTS) and the rostral ventrolateral medulla (RVLM) maintain blood pressure in the event of position changes3.The drop in blood pressure (BP) when standing up reduces the blood flow going to the inner ear subsequently causing ischemic excitation of the peripheral vestibular hair cells, which leads to the excitation of central vestibular nuclei thereby causing vertigo after hypotension. In addition, the excitation of the vestibular nucleus following the hypotension induces vestibulosympathetic reflex (VSR), and the reflex regulates blood pressure with a dual control  mechanism4.Diagnosis of hemodynamic orthostatic dizziness/vertigo requires: (A) five or more episodes of dizziness, unsteadiness or vertigo triggered by arising or present during upright position, which subsides by sitting or lying down; (B) orthostatic hypotension, postural tachycardia syndrome or syncope documented on standing or during head-up tilt test (HUTT); and (C) not better accounted for by another disease or disorder5.Orthostatic hypotension (OH) is a disease of orthostatic vertigo, refers to cases where the systolic blood pressure drops by at least 20 mmHg, or the diastolic blood pressure drops by at least 10 mmHg within 3 min of standing up after lying down, and is diagnosed by measuring blood pressure7.It is known that repeated occurrence of OH may result in hypoperfusion of the brain, which is responsible for the central nervous system, and cause blood flow insufficiency in the brainstem and the inner ear9. In this study, how OH and BPPV are associated with each other will be examined.Recent studies have shown that BPPV-induced otolith organ hypofunction can cause transient OHSince hypertension, diabetes, drugs, age, etc., known as the causes of OH are also known as risk factors for BPPV, this study is intended to verify the hypothesis that the OH seen when BPPV occurred may act as a marker of otolith organ hypofunction and thereby becoming a factor that affects the recurrence of BPPV.This retrospective study was conducted with patients diagnosed with BPPV among patients who visited the One Otorhinolaryngology Clinic due to a symptom of vertigo from September 2020 to August 2021. When a patient who visited the hospital due to a symptom of vertigo showed any abnormal finding in the medical history taking, general otolaryngological examination, and physical examination using frentzel glass, the following tests were carried out immediately.All patients did not intake alcohol within 12 h of the test, and drugs such as high blood pressure and diabetes, excluding stabilizers, were taken as usual.After resting for at 15 min in a quiet room, the patient was laid down on the test table.As for the sequence of the test, the blood pressure and pulse rate were measured twice at 1-min interval after resting for 3 min in a lying position, the table was raised to 70° for 30 s thereafter, the blood pressure and pulse rate were measured three times at 1-min intervals, and the patient was diagnosed with OH in case where the systolic blood pressure dropped by at least 20 mmHg or the diastolic blood pressure dropped by at least 10 mmHg. In cases where the patient felt severe vertigo during the test, the test was immediately stopped. In addition, all patients were subjected to a positional test and a positioning test using videonystagmography test. Posterior canal BPPV was diagnosed by observation of torsional upbeating nystagmus following Dix-Hallpike test. Horizontal nystagmus induced by supine roll test was considered as diagnostic sigh for lateral canal BPPV. Anterior canal BPPV is diagnosed when Dix-Hallpike positioning produces a down-beating nystagmus with torsional component. After diagnosis with otolithiasis, repositioning maneuvers were performed twice a week, and treatment was terminated when symptoms disappeared and the nystagmus was resolved based on video frentzel glass examination. All patients were diagnosed and treated by a physician.Recurrence was diagnosed with symptoms that occurred one month after the end of the treatment and nystagmus confirmed with video frentzel glass, and treatment was carried out again.During the study period, there were 256 patients with idiopathic BPPV. Of them, two patients were unable to undergo HUTT, one patient was excluded due to past varicose vein surgery, and 14 patients were excluded due to a past history of BPPV. Finally, 239 patients were studied, and the average follow-up period was 9.1 months , which are variables investigated in the study.Through Breslow-Day's test for homogeneity, age, drug use, hypertension, and diabetes passed the homogeneity test. In the tests of conditional independence, the Mantel–Haenszel test value was p = 0.963. Based on this, a model suitable for the study was designed. First, binary logistic regression analysis was performed to identify factors affecting OH among the study subjects, and polychotomous logistic regression analysis was used to study the effects of OH on BPPV recurrence. The fit of the model was p = 0.006, and polychotomous logistic regression analysis was carried out in the ascending method based on the multiple recurrence group among no recurrence group, single recurrence group, and multiple recurrence group. The model verified main effects, and finally, the overall statistical difference for the variables in the polynomial logistic regression analysis was verified through the Wald test using covariance. Statistical analyses were conducted using IBM SPSS ver. 19.0 . Statistical significance was considered to exist when p < 0.05.As shown in Table Drug-taking also had a significant effect on OH. It was shown that drug-taking increased the risk of OH occurrence by 4.08 times : 1.20–13.77) compared to the group that did not take drugs.Sex, hypertension, and diabetes did not have any significant effect on the occurrence of OH in this study.The characteristics of patients in each group are shown in Table As shown in Table In addition, age, sex, hypertension, and diabetes did not show any significant difference in the risk of recurrence in both the no recurrence group and the single recurrence group compared to the multiple recurrence group. In conclusion, age, sex, hypertension, diabetes, OH, and drug-taking did not make any significant difference in the risk of recurrence among the three groups, and no statistically significant risk was observed.2. Stimulation of the vestibular system according to posture changes lead to the excitation of the otolith organ and the relevant signals are transmitted to the NTS and the RVLM via the vestibular nucleus complex through the sympathetic nervous system. The information integrated in RVLM functions to maintain blood pressure.Blood pressure is maintained by a combined mechanism of the baroreceptor reflex and the vestibulosympathetic reflex. The baroreceptor reflex of the carotid sinus is transmitted to the NTS through the glossopharyngeal nerve, and the baroreceptor reflex of the aortic arch is transmitted to the NTS through the vagus nerve4.According to the guidelines of the Bárány society, OH is defined by a significant reduction in systolic (> 20 mmHg) and/or diastolic (> 10 mmHg) blood pressure within 3 min upon standing from sitting or during head-up tilt test. It may cause orthostatic dizziness/vertigo or not. Although the most common cause of orthostatic dizziness/vertigo is probably OH, it is not the only cause. Thus, the nomenclature, orthostatic dizziness/vertigo and OH, should be used distinctively. Orthostatic dizziness/vertigo is a symptom while OH is a disorder11. OH have been explained by a decline of venous return associated with muscle weakness, the decrease in fluid volume, the increase of venous compliance, dysfunction of the baroreceptor and the degradation of cardiac performance12. Orthostatic hypotension is common in those who are age 65 and older. Special cells near heart and neck arteries that regulate blood pressure can slow as aging. It also may be harder for an aging heart to speed up and compensate for drops in blood pressure. The otolith organs are vulnerable to degradation due to aging, and the vestibulocardiovascular response may be diminished with age13.A large population-based study on OH during postural testing in adults aged > 20 years showed an overall OH prevalence of 4.8–9% but increased to 10–20% in elderly people10. In this study, age also had a statistically significant effect on the occurrence of orthostatic hypotension  patients out of 102 patients had OH, and the prevalence was equal to the general prevalence. The findings of the foregoing study indicated that orthostatic dizziness symptoms were not related to OH in BPPV patients, that BPPV was the most common cause of orthostatic dizziness symptoms, and that the ratio of OH was the highest among orthostatic intolerance patients. Jeon et al. also assumed that impairment of VSR in BPPV was a cause of OH.On reviewing the previous studies on OH and BPPV, it can be seen that all the studies were conducted with patients with OH and post BPPV. In a study conducted by Jeon et al.8, when post-BPPV patients were studied with a group with vertigo symptoms and a group without vertigo symptoms, 11 out of 58 patients (19%) were OH patients, and the group with vertigo symptoms had significantly more OH patients. Interestingly, the foregoing study showed a higher ratio of OH compared to other studies because it used continuous BP monitoring. Kim et al. explained that continuous BP monitoring is a more sensitive test compared to BP monitoring at 1-min intervals because it can observe brief episodes of transient OH.In a study conducted by Kim et al.In the study conducted by Kim et al., the medical history and drug-taking of patients with OH were investigated, and contrary to our study, it was concluded that the possibility for drugs or medical history to cause OH in BPPV patients was very low.9, the OH co-occurrence rate of patients with residual dizziness after BPPV treatment was 34%, which was significantly higher than that of the general population. However, the presence or absence of OH was not statistically related to age, gender, or symptoms of dizziness, and the number of samples was not large. The study conducted by Pezzoli also speculated that OH occurred because abnormalities in the otolith organs affected the control of the sympathetic nerves including the VSR.In a study conducted by Pezzoli et al.14 reported that the absent vestibular evoked myogenic potential group had a significantly higher ratio of OH and that this supported the hypothesis that otolith organ dysfunction induces OH. However, BPPV does not immediately mean the dysfunction of the otolith organ, and if the dysfunction due to the degeneration of the otolith organ causes OH, there may be an indirect relationship between otolith organ dysfunction and OH but it is not clear to what extent the otolith organ dysfunction affects the occurrence of OH 1 min after standing up in the HUTT test because the blood pressure drop due to VSR disorder affects the occurrence of OH within several seconds after standing up, earlier than the baroreceptor.In a study conducted with 248 patients with vertigo under the age of 65 years, Aoki et al.This study began with the following questions. A hypothesis that the importance of metabolic diseases such as hypertension and diabetes as risk factors for BPPV are growing and since these risk factors commonly affect the occurrence of OH, there may be some relationships between OH and BPPV.13, the prevalence of OH is significantly higher than that of BPPV so that the hypothesis that OH affects the otolith organ and can affect the occurrence or recurrence of otoliths was considered more reasonable.The hypothesis of other studies that OH may occur temporarily due to the dysfunction of the otolith organ partially agrees that BPPV may act as a risk factor for the occurrence of OH, but since the annual prevalence of BPPV is around 1%Therefore, contrary to the existing hypothesis, a hypothesis that OH may affect BPPV was established to conduct this study.In this study, age and drug-taking were observed to be statistically significant as factors affecting the occurrence of OH in the BPPV patient group using logistic regression analysis. Although both factors were previously known as risk factors for OH, this study can be said to be significant in that it showed the same result in BPPV patients too. The age variable used in this study is a confounding variable that is causally related to the occurrence and recurrence of BPPV and OH, and it also has the nature of an effect modifier. An effect modifier refers to a confounding variable that causes different degrees of disturbance depending on its layers. Also drug-taking may be a confounding variable. Age and drug-taking can be said to act as confounding variables and as effect modifiers.In a comparison of the three groups using polychotomous logistic regression analysis Table , the risIn addition, the effect of drugs on the recurrence of BPPV is a newly discovered area. To this author’s knowledge, few studies have mentioned the effect of drugs as a factor for recurrence of BPPV. The study findings indicating that the risk of recurrence was reduced between the no recurrence group and multiple recurrence group when drugs such as heart disease drugs, depression drugs, sleeping pills, thyroid drugs, and prostate drugs investigated in this study were not taken.6.There are studies on spontaneous intracranial hypotension (SIH) that can explain the mechanism by which OH affects the otolith organs. It is well known that SIH causes audiovestibular impairmentsIn a study conducted by Choi et al., 62% of SIH patients showed audiovestibular impairment, and SIH patients showed peripheral type nystagmus, which was thought to have been caused by endolymphatic hydrops and irritation of the vestibulocochlear nerve.15. When patients experience SIH, the decreased CSF pressure is directly transmitted to the perilymph, resulting in compensatory endolymphatic hydrops mimicking Menière’s disease. Then hydropically induced damage to the maculae of the utricle and saccule may predispose patients to BPPV16.In a study by Xia et al., too, venous engorgement in the brain was identified as a factor for the development of BPPV in patients with SIH, and low cerebrospinal fluid (CSF) pressure was also associated with the development of BPPVThere are two possible mechanisms which can be thought to be the mechanisms through which OH causes BPPV.First, the reduction of the perilymph due to CSF hypovolemia would result in compensatory endolymphatic hydrops that will in turn generate vertigo and auditory dysfunction.Second, there is an assumption that the irritation of the vestibular and cochlear nerves that are present in the internal acoustic canal due to the venous engorgement that occurred in the internal acoustic canal affects the otolith organ.17. As such, it is speculated that the hypofunction or dysfunction of the otolith organ according to the two mechanisms that can be caused by OH may act as a trigger or risk factor for BPPV. In addition, the aspect that orthostatic headache persists for several months after treatment of SIH patients was speculated as indicating that the recovery from the imbalance between CSF and endolymph takes quite a long time17. Therefore, it is assumed that in the case of OH found when BPPV occurred, the momentary decrease in perfusion due to the hypovolemic state may lead to an unexpectedly long time for the recovery of the otolith organ and may affect the recurrence later.The venous engorgement of the internal acoustic canal has been identified in magnetic resonance imaging studies18. For this reason, they often feel vertigo similar to BPPV symptoms, and the threshold for feeling dizziness is lowered so that it is difficult for them to feel symptoms such as vertigo. The hypofunction of the otolith organ due to the influence of OH, etc. is thought to make the patient unable to detect vertigo due to positional changes well, and the old BPPV in turn affects the sympathetic nervous system, which in turn creates a vicious cycle that adversely affects the otolith organ. There is evidence from studies conducted on animals and humans that vestibular lesions result in a diminished VSR and consequently in an increased intolerance to the orthostatic position9.For similar reasons, BPPV patients with cardiovascular disease such as hypertension show a low ratio of first feeling postural vertigo and take longer to diagnosis19.In this study, HUTT, a passive standing method, was measured at 1-min intervals. There are two methods of tests for measuring OH: the active standing test and the passive standing test. The two methods may have different blood pressure responses. Most studies have used the active standing test, but many elderly people cannot easily convert from the lying position to the standing position. Therefore, it is difficult to accurately measure changes in blood pressure during active standing test, especially in the elderly, and HUTT is considered to be an easier test through which it is easier to detect OH14. Therefore, the OH found during HUTT reflects the abnormalities of the overall autonomic nervous system rather than the function of the otolith organ.In the case of active standing, the lower extremity muscles are used to sufficiently stimulate the sympathetic nervous system thereby inducing vestibular sympathetic reflexes, but the foregoing is not the case in the case of passive standing so that the drop in blood pressure may be smaller20. Therefore, the blood pressure fall that meets the OH standard in the HUTT measurements at intervals of 1 min is not completely explained by the abnormality of the vestibular sympathetic nervous system reflex due to the dysfunction of the otolith organ. This is because, in general, blood pressure response due to vestibular dysfunction occurs within 30 s14.HUTT does not reflect all patients' vertigo, because the blood pressure measurements at intervals of 1 min during HUTT cannot measure all of the VSR or baroreceptor activities that occur within a few seconds. Vestibular influences on the cardiovascular system operate within one heartbeat after the onset of abrupt head acceleration and VSRs may operate at a latency of 0.4 sThis study is the first study that studied the effect of OH on the recurrence of BPPV and showed the possibility that OH could partially influence the recurrence of BPPV. The conclusions of this study about the relationship between OH and BPPV means that the absence of OH is related to the absence of recurrences.It was difficult to statistically organize common factors that exist between OH and BPPV. If the number of samples in the multiple recurrence group was large, it is thought that the effects of the variables could be known more clearly. Advanced studies with more samples are thought to be necessary.Supplementary Tables.


Introduction: The risk factors influencing the natural course of chronic kidney disease (CKD) are complex and heterogeneous. Recognizing the factors associated with CKD progression can enable the identification of high-risk patients for more intensive treatment.Patients and methods: A retrospective evaluation of CKD patients was performed under follow-up between January 1, 2001 and December 31, 2016 at a tertiary health care center.Results: Among 5370 screened patients, 1020 patients with complete data were included in the analysis. The median follow-up period for the studied patients was 9.3 years. Based on the analysis, 120 (11.8%) patients had reached end-stage kidney disease “ESKD” or death. The study revealed that the risk factors associated with reaching ESKD and/or death using Kaplan–Meier survival curve and log rank test included higher hemoglobin A1c among diabetic patients, higher grade of proteinuria, and non use of renin-angiotensin system blockers. The patients with CKD progression constituted 77.2% of all CKD patients. The study findings indicated that older age, Arab ethnicity, smoking habit, diabetes mellitus and hypertension  are among the significant risk factors associated with a further decline of the estimated glomerular filtration rate (eGFR) and further CKD progression.Conclusion: This study summarized the demographic and clinical risk factors associated with CKD progression and patients’ outcomes among a unique and heterogeneous population in the state of Qatar. Intensive treatment of modifiable risk factors could be of value in halting the progression of CKD. However, prospective studies are warranted to confirm our findings. Moreover, CKD resulted in 1.2 million deaths and was the 10 The estimated risk factors of CKD progression causing morbidity and mortality have been studied across different ethnic and racial populations, showing important differences between them. In the United States, for instance, the rate of renal replacement therapy (RRT) initiation for end-stage kidney disease (ESKD) is disproportionately higher for ethnic minority groups  when compared to that for Caucasians, despite the similar prevalence for early stages of CKD.The risk factors influencing the natural course of CKD are complex and heterogeneous and there are only a few systematic studies that have focused on this issue.The economic development experienced in Qatar has been associated with inappropriate dietary and lifestyle patterns that led to increased rates of obesity and chronic non communicable diseases. Furthermore, this situation can be associated with a surge in international migration of workers from developing countries, as evidenced by the annual population growth of 18.9% from 2008 onward.The present work aimed to study the distribution of CKD in Qatar's heterogeneous population that has been followed in nephrology clinics to examine the prevalence of risk factors associated with CKD progression as well as to describe the relevant clinical outcomes (such as death or end-stage kidney disease) over a long observation period. Patients diagnosed with CKD of different stages on at least 2 occasions and lasting >3 months were included. All patients with albuminuria  or equivalent (protein-to-creatinine ration >15 mg/mmol or urine protein reagent strip 1+ or more), on at least 2 occasions, lasting >3 months, were also included. All outpatient eGFR measurements until the end of the study were utilized, excluding the laboratory measurements associated with any hospital admission.A retrospective evaluation of CKD patients under follow-up at a tertiary health center  was conducted. In this study, we reviewed the electronic medical records of all patients visiting the nephrology clinics between January 1, 2001 and December 31, 2016. The estimated glomerular filtration rate (eGFR) for each patient was calculated from the serum creatinine level using the CKD-Epidemiology Collaboration equation.The identified CKD patients were screened for demographic data, including their age, gender, nationality, and ethnicity. Body mass index (BMI) was calculated for each patient as the body weight measured in kilograms, divided by the height squared meter. The date of diagnosis of CKD and eGFR at the time of diagnosis was recorded. Follow-up renal function until the last follow-up visit was performed yearly, and it included yearly registered values of eGFR for any individual patient plus the degree of albuminuria/proteinuria . Further categorization of the eGFR and albuminuria grades for each value/year/patient was conducted as per the Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (KDIGO) classification.The cause of CKD for each patient was retrieved from the patient's file as per the primary nephrologist assessment. In addition, the comorbid conditions, including diabetes mellitus, diabetes complications, hypertension, dyslipidemia, cardiovascular diseases, cerebrovascular disease, or peripheral vascular disease, were also assessed.– Age ≥ 18 years at the time of inclusion.– All patients diagnosed with CKD according to the KDIGO classification.– Follow-up period with available laboratory data for ≥ 2 years.– Follow-up period < 2 years.– Patients who required initiation of RRT shortly after the presentation.– Insufficient data, including:• unidentified cause of CKD• unavailable renal function test data for >2 years during the follow-up– Initiation of RRT in the form of hemodialysis, peritoneal dialysis, or preemptive kidney transplantation– Patient's death– eGFR progression:Patients were classified as per their eGFR difference between the values at the time of inclusion and the last follow-up, as follows: patients with eGFR decline  and patients without .– eGFR decline expressed in mL/min/per year for those with CKD progression:eGFR decline per year was calculated by dividing the eGFR difference (at the time of inclusion and the last follow-up) by the follow-up period in years.– Albuminuria or proteinuria progression2, or death. Kaplan–Meier analysis with the log rank test was used to assess the association of primary outcome events with different measured variables. p ≤ 0.05 was considered to indicate statistical significance.Data were presented as the means ± standard deviation for continuous variables and as the numbers or percentages for categorical variables. Patients were followed in survival analysis from the date of CKD diagnosis until the last follow-up or the occurrence of primary outcome events, including the start of RRT, kidney transplant, eGFR < 10 mL/min/1.73 mIn total, 5370 patients visited the nephrology outpatient department at a tertiary health care center between January 1, 2001 and December 31, 2016. A total of 1369 patients were excluded because they had < 2-year of the follow-up period. Further 2981 patients were excluded for incomplete data. The remaining 1020 patients with complete data were included in the analysis. The mean ± SD and median follow-up periods for the studied patients were 9.6 ± 3.8 and 9.3 years, respectively (range: 2–17 years) .One hundred and twenty (11.8%) patients reached the primary outcome (ESKD or death) after a mean follow-up of 9.6 years .p < 0.05). Furthermore, DM and/or HTN, as a cause of CKD, was significantly associated with eGFR decline, when compared to other causes (p = 0.0001). For DM, higher hemoglobin A1c acted as a significant risk factor for eGFR decline, while, for HTN, the more the number of anti-hypertensive medications, the greater the ratio of eGFR decline. For all CKD patients, higher albuminuria grade and non use of ACEI/ARBs were significantly associated with more patients experiencing eGFR decline. All associated co morbidities were coupled with further eGFR decline, except for cerebrovascular accidents, which did not reach any statistical significance.2/year) when compared to others. Furthermore, a higher degree of albuminuria, non use of ACEI/ARBs, and higher hemoglobin A1c level were associated with greater eGFR decline, reaching 3.2, 3.3, and 4.1 mL/min/1.73 m2/year, respectively.For patients who experienced eGFR decline, further analysis was performed. For the analysis of risk factors associated with ESKD or death using the Kaplan–Meier survival curve and log rank test, we noted that higher albuminuria, higher A1c, and non use of ACE/ARBs were associated with a statistically high significance and increased incidence of these outcome events –4. On thIn this study, a long follow-up period associated with informative electronic medical files allowed the investigators to identify the clinical risk factors associated with CKD progression and those associated with ESKD/patient death over a prolonged period when compared to other similar studies. Among our studied group of CKD patients, CKD progression was found to be associated with patients’ certain demographics and disease-related risk factors. Regarding the Arab racial preponderance, although non communicable diseases including diabetes, hypertension, and obesity are highly prevalent in the Arab world, there is very limited data available on the exact prevalence of various kidney diseases in the Arab population. One recent report from Palestine showed that CKD is highly prevalent among type 2 diabetic adults and that comorbid hypertension, smoking, and older age increase the risk of developing CKD. For patients with CKD, there has been a lack of studies on the association between smoking and CKD progression, and the limited literature has yielded conflicting results. However, in a recent prospective cohort study involving Korean CKD patients, smoking was found to be associated with a significantly higher risk of worsening kidney function.Patient-related factors in our study included older age (particularly >60 years), Arab ethnicity, or being a smoker. Older age is associated with the occurrence and higher progression of CKD by multiple studies. In our study, there was no gender effect on CKD progression. Some previous studies have indicated no gender differences in the progression of nephropathy among patients with diabetes. Other studies have shown that the male gender predicted the progression of renal disease in patients with diabetes, while others reported a detrimental effect of the female gender on the progression of diabetic nephropathy.In a systematic review and meta-analysis with a follow-up duration of 1.5–16 years, it was found that being male, having substantial proteinuria, and having diabetes were associated with increased hazards of progression to ESRD. However, in contrast to our findings, the present finding mainly suggested the development of micro or macro albuminuria, with no effect on doubling the serum creatinine level. Other relatively small-sized studies reported no association between the baseline HbA1c level and renal outcomes. Therefore, a relatively long-term follow-up of our patients might have shown the long-term effect of Hb A1C in association with rising serum creatinine levels.Disease-related factors, associated with CKD progression in the current study, included having type 2 diabetes and hypertension , diabetic retinopathy, diabetic neuropathy, diabetic foot, cardiovascular disease, or advanced CKD at the time of diagnosis. Furthermore, diabetes mellitus was found to be associated with greater CKD progression when associated with a higher Hb A1C. Intensive glucose control has previously been demonstrated to be associated with a significant reduction in renal events in patients with type 2 diabetes in the Action in Diabetes and Vascular Disease study.In our study, hypertension was found to be associated with greater CKD progression when the patient was treated with more numbers of anti-hypertensive medication (reflecting more severe hypertension) and if antihypertensives were not including ACEIs or ARBs. This finding is supported by several studies demonstrating the beneficial effects of blood pressure control and other benefits with the use of ACEs/Arbs in reducing renal events. In our study, CKD progression was associated with CVDs including congestive heart failure, coronary artery disease, or peripheral vascular disease (but not cerebrovascular accidents).The association between kidney disease progression and cardiovascular disease (CVD) risk was assessed among patients with type 2 diabetes and CKD in a UK primary healthcare setting to reveal that progression of CKD is possibly associated with CVD risk, in which increased risk of cardiovascular events was noted among those with the fastest rate of eGFR decline, most predominantly in heart failure cases.Advanced CKD presentation including higher albuminuria stage and higher creatinine level was associated with more CKD progression. The presence of proteinuria, the major marker of kidney damage, is the best-known risk factor for CKD progression. Several studies have recorded observed that proteinuria was associated with a faster rate of kidney function decline and the achievement of ESRD.2/year) as original kidney disease, to have a higher grade of albuminuria ( − 3.2 ± 2.4 mL/min/1.73 m2/year), high HbA1c (>10% was associated with an eGFR decline of − 4.1 ± 6.2 mL/min/1.73 m2/year) and not being on any medication for renin-angiotensin system block ( − 3.3 ± 3.7 mL/min/1.73 m2/year).In our study, greater eGFR decline was found to be associated with having both diabetes and hypertension  are among the significant risk factors associated with greater eGFR decline and CKD progression.Supported by a grant from Medical Research Center, #17195/17, Hamad Medical Corporation, QatarThe study was approved by the local ethical committee of the Hamad Medical Corporation research center, under research study number #17195/17 in accordance with the relevant guidelines and regulations. Patients’ consent was inapplicable as the study was designed to be a retrospective evaluation of preexisting medical data from registries and electronic medical reports with no human interventions. Patients` confidentiality was preserved.AvailableNone to discloseContributing authors have shared in data collection and manuscript review.The authors acknowledge HMC medical research center, nephrology ward staff, and coordinators for their assistance.


Symptomatic intracranial hemorrhage (sICH) is a terrible complication after intravenous alteplase in stroke, and numerous biomarkers have been investigated. However, the change of biomarkers to sICH has not been well determined.To investigate the association between the change of biomarkers and sICH.This is a prospective cohort study, and patients with sICH within 24 h after thrombolysis were enrolled, while patients without sICH were matched by propensity score matching with a ratio of 1:1. The blood samples were collected before and 24 h after intravenous thrombolysis (IVT), and preset 49 serum biomarkers were measured by microarray analysis. Protein function enrichment analyses were performed to detect the association between the change of biomarkers and sICH.Of consecutive 358 patients, 7 patients with sICH in 24 h were assigned to the sICH group, while 7 matched patients without any ICH were assigned to the non-sICH group. A total of 9 biomarkers were found to significantly change before vs. after thrombolysis between groups, including increased biomarkers, such as brain-derived neurotrophic factor, C-C motif chemokine ligand (CCL)-24, interleukin (IL)-6, IL-10, IL-18, and vascular endothelial growth factor, and decreased biomarkers, such as CCL-11, intercellular adhesion molecule-1, and IL-7.This is the first study to identify changes in serum biomarkers in patients with sICH after IVT, and found that 6 neuroinflammatory and 3 neuroprotective biomarkers may be associated with brain injury following post-thrombolytic sICH.https://www.clinicaltrials.gov, identifier: NCT02854592. Intravenous alteplase is the main effective treatment for acute ischemic stroke (AIS) within 4.5 h after the onset of symptoms . SymptomMountains of studies have investigated predictors for post-thrombolytic sICH in stroke, such as clinical, radiological, and laboratory factors –5. AlthoIn the INtravenous Thrombolysis REgistry for Chinese Ischemic Stroke within 4.5 h of onset (INTRECIS) , 5 centeFrom August 2018 to July 2019, patients receiving intravenous thrombolysis (IVT) within 4.5 h after symptoms onset were consecutively screened to collect blood samples before thrombolysis at five pre-set stroke centers in the INTRECIS study. The INTRECIS is a prospective, nationwide, multi-center, and registry study of consecutive adult patients who were eligible for treatment with IVT within 4.5 h of the onset of symptoms, and has been published recently . PatientThe baseline characteristics and clinical data of recruited patients were obtained from the electronic database: age, current smoking, alcohol consumption, gender, systolic blood pressure, diastolic blood pressure, symptom onset-to-treatment time, blood glucose, National Institutes of Health Stroke Scale (NIHSS) score at admission, previous use of antiplatelet, and medical history, and the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. All patients underwent a CT scan at admission and 24 h  after IVT, to evaluate the presence of ICH. According to European Cooperative Acute Stroke Study (ECASS)-II study, sICH was defined as an increase of ≥4 on the NIHSS scores caused by ICH within 36 h .The methods of laboratory determinations were described in our previous study . Brieflyt-tests were used to analyze continuous variables with normal distribution. Additionally, categorical variables were described as numbers and proportions. Categorical variables included gender, medical history, and TOAST classification. The Pearson χ2 tests were used to analyze categorical variables.Descriptive statistics were performed to compare variables between the two groups. Continuous variables with normal distribution were described as means and standard deviation (SD). Continuous variables included age, systolic blood pressure, diastolic blood pressure, blood glucose, NIHSS score, symptom onset to thrombolysis time, and detected circulating concentration of biomarkers. The p (BH method) based on moderated t statistics. In all analyses, differences were considered statistically significant with a p < 0.05. The free statistical language R (version 3.10.3) was used for the outcomes and graph in microarray analysis.The empirical Bayes-based linear model method was used to analyze the differential expression of biomarkers between different stages of disease with the R package limma. The differential expression was evaluated by adjusting the value of As shown in p < 0.05), including a significant increase in brain-derived neurotrophic factor (BDNF), C-C motif chemokine ligand (CCL)-24, interleukin (IL)-6, IL-10, IL-18, and vascular endothelial growth factor (VEGF), and a significant decrease in IL-7, intercellular adhesion molecule (ICAM)-1, and CCL-11  enrichment analysis was used to gain a deeper insight into the main functions of the identified biomarkers. The GO analysis consisted of biological processes, molecular functions, and cellular component analysis. The biological process analysis showed that ICAM-1, IL-6, IL-7, IL-10, IL-18, and VEGF were mostly included in the positive regulation of cell adhesion . The molBased on the information from the Search Tool for the Retrieval of Interacting Genes (STRING) database, the protein–protein interaction network constructed by the above 9 identified biomarkers was obtained . The resTo the best of our knowledge, this is the first report that identified significant changes in 9 serum biomarkers in a sICH group compared with those in a non-sICH group, including increased biomarkers, such as BDNF, CCL-24, IL-6, IL-10, IL-18, and VEGF, and decreased biomarkers, such as CCL-11, ICAM-1, and IL-7.There have been a lot of studies to investigate the association of biomarkers with post-thrombolytic hemorrhagic transformation in stroke –11. HoweIn the present study, we found significantly decreased circulating levels of IL-7, ICAM-1, and CCL-11 in the sICH patients, compared with non-sICH patients, which is consistent with previous studies –19. AfteOur study also found that CCL-24, IL-6, and IL-18 significantly increased after sICH, compared with patients with non-sICH. These biomarkers act as proinflammatory factors and express in the recruited leukocytes and activated glia. For example, CCL-24 was found to act directly on chemokine receptor CCR-3 to recruit leukocytes and play a role in mediating the neuroinflammation set off by ischemic-reperfusion injury , 30. IL-In addition, BDNF, IL-10, and VEGF were significantly increased after sICH, which was consistent with previous studies –37. BDNFUnexpectedly, we did not detect significant changes in other preset biomarkers, such as MMP-9 and ferritin, which were previously reported to be associated with post-thrombolytic hemorrhagic transformation in ischemic stroke . The negBased on functional enrichment analysis, cell adhesion positive regulation, cytokine activity, extracellular matrix, and cytokine–cytokine receptor interaction were significantly enriched items. After a stroke, adhesion molecules  mediated several leukocytes and cytokines  entered into the brain through the injured blood-brain barrier , 22. TheWe acknowledge that our study has several limitations. First, it is a small-sample study with only 7 AIS patients with post-thrombolytic sICH in 24 h and collecting blood samples. Additionally, the study only collected blood samples before and 24 h after IVT. A large cohort study with samples collected at more time points  is warranted. Second, only serum biomarkers were measured in the present study. Given the neuroinflammation-related or neuroprotection-related biomarkers, it may provide valuable information if these biomarkers are measured in the brain such as CSF. Third, the sensitivity and specificity of identified biomarkers for predicting sICH need to be validated in the future. Fourth, the change of biomarkers in patients with different etiologies should be investigated in the future. Finally, although baseline data were matched through propensity scores matching, some potential biases may be inevitable. For example, there may exist an imbalance in the baseline circulating levels of biomarkers.For the first time, the present study prospectively investigated the changes of preset 49 serum biomarkers in patients with ischemic stroke receiving thrombolysis and found that 6 neuroinflammatory and 3 neuroprotective biomarkers were involved in the brain injury following post-thrombolytic sICH. The role of these biomarkers warrants further investigation given the potential therapeutic implications.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Institution Human Research Ethics Committees of General Hospital of Northern Theater Command. The patients/participants provided their written informed consent to participate in this study.H-SC designed and reviewed. YC conducted the analyses and drafted the manuscript. X-HW, YZ, S-YC, B-YS, and L-HW contributed to the implementation of blood sample collection. All authors contributed to the article and approved the submitted version.The study was funded by grants from the National Key R&D Program of China (2017YFC1308203) and the Project on Research and Application of Effective Intervention Techniques for Chinese Stroke Guidelines from the National Health and Family Planning Commission in China (GN-2016R0008).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In the distal lung, small airways and vessels share a common microenvironment, where biological crosstalks take place. Because respiratory cells infected by viruses express a number of molecules with potential impact on airway and vascular remodeling, we decided to test the hypothesis that CCC patients carrying viral genomes in the airways might be at a higher risk for pulmonary (and systemic) hemodynamic disturbances postoperatively.Pulmonary vascular abnormalities pose a risk for severe life-threatening hemodynamic disturbances following surgical repair of congenital cardiac communications . Preoperative pulmonary/systemic mean arterial pressure ratio (PAP/SAP) was 0.78 (0.63–0.88). The presence or absence of genetic material for respiratory viruses in nasopharyngeal and tracheal aspirates was investigated preoperatively in the absence of respiratory symptoms using real-time polymerase chain reaction (kit for detection of 19 pathogens). Post-cardiopulmonary bypass (CPB) inflammatory reaction was analyzed by measuring serum levels of 36 inflammatory proteins (immunoblotting) 4 h after its termination. Postoperative hemodynamics was assessed using continuous recording of PAP and SAP with calculation of PAP/SAP ratio.p = 0.011) with a PAP/SAP of 0.44 (0.36–0.50) in patients who were positive versus 0.34 (0.30–0.45) in those who were negative (p = 0.008). The presence or absence of viral genomes in nasopharynx did not help predict postoperative hemodynamics. Postoperative PAP/SAP was positively correlated with post-CPB levels of interleukin-1 receptor antagonist (p = 0.026), macrophage migration inhibitory factor (p = 0.019) and monocyte chemoattractant protein-1 (p = 0.031), particularly in patients with virus-positive tracheal aspirates.Viral genomes were detected in nasopharynx and the trachea in 64% and 38% of patients, respectively. Rhinovirus was the most prevalent agent. The presence of viral genomes in the trachea was associated with an upward shift of postoperative PAP curve (s carrying respiratory viral genomes in lower airways are at a higher risk for postoperative pulmonary hypertension, thus deserving special attention and care. Preoperative exposure to respiratory viruses and post-CPB inflammatory reaction seem to play a combined role in determining the postoperative behavior of the pulmonary circulation.Patients with CCC In patients with congenital cardiac communications, pulmonary vascular abnormalities pose a risk for immediate postoperative hemodynamic disturbances which are sometimes severe enough to be considered as life-threatening medical emergencies. Besides, persistent pulmonary hypertension late after operation may affect treatment success –3. The sLarge (unrestrictive) cardiac communications may be associated with pulmonary overcirculation with variable degrees of pulmonary congestion. Patients may present with congestive heart failure and failure to thrive and are predisposed to recurrent upper and lower respiratory tract infections. Viral infections have been extensively investigated in pediatric patients undergoing cardiac surgery. They were shown to impact on major outcomes, such as duration of postoperative mechanical ventilation, length of intensive care unit and hospital stays, and mortality –10. HoweRespiratory viral infections may affect pulmonary microcirculation in at least two ways. First, they may cause local alveolar hypoxia, a major stimulus for pulmonary vasoconstriction. Second, infected airway epithelial cells cause cascade expression of proinflammatory cytokines, chemokines and growth factors, thus inducing local inflammation, extracellular matrix reorganization and cell proliferation –17. BecaIn this study, we investigated the possible role of preoperative exposure to respiratory viruses and post-CPB inflammatory reaction in determining the behavior of the pulmonary circulation following elimination of left-to-right cardiac shunts. We examined that in a prospective pediatric cohort taking into consideration classical risk factors for postoperative pulmonary hypertension as well. We also looked for a possible relationship between the presence/absence of viral genomes in the airways prior to surgery and the level of pulmonary arterial pressure after discharge from the hospital.This was a prospective cohort study comprising patients who were admitted to the Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo Brazil, from November 2016 to September 2021, for surgical repair of congenital cardiac communications. Patients were consecutively enrolled based on the following criteria: age 1 month to 3 years; heart with biventricular physiology; presence of unrestrictive cardiac communications, i.e., with a diameter of the post-tricuspid communication greater than 50% of the aortic annulus diameter on transthoracic echocardiography; absence of pulmonary stenosis; clinical features suggestive of at least moderately elevated pulmonary arterial pressure: a loud second heart sound at pulmonic region, increased pulmonary/systemic blood flow ratio with absence of significant pressure gradients across the septal defects (echocardiography) and increased pulmonary vascular markings on chest radiographs; absence of extracardiac syndromes other than Down syndrome; and absence of any signs of ongoing or recent inflammatory or infectious diseases. The study was based essentially on patients who were eligible for surgical treatment with no need for cardiac catheterization. Patients with significant right-to-left shunting and persistently low peripheral oxygen saturation (< 85%), suggesting the presence of advanced pulmonary vasculopathy, were not included. An informed consent signed by family members was necessary for patient inclusion. The study protocol was approved by the Institutional Scientific and Ethics Committee, CAPPesq no. 3.735.675.Data recorded at baseline included details of the clinical history and physical examination, such as signs and symptoms of congestive heart failure and failure to thrive, presence or absence of Down syndrome, occurrence of acute respiratory infections and eventual hospitalization prior to referral to the Heart Institute. The diagnosis of Down syndrome was confirmed by genetic testing. Chest radiographs, ECG and complete echocardiographic data were available for all patients. Transthoracic echocardiography was used to assess cardiovascular anatomy and blood flow parameters. The pulmonary/systemic blood flow ratio was calculated based on systolic flow parameters in the right and left ventricular outflow tracts. Pulmonary venous flow was estimated by measuring the velocity–time integral of blood flow in pulmonary veins. Patients with a pulmonary blood flow ratio greater than 2.50 and a velocity–time integral of pulmonary venous flow > 24.0 cm were considered to have pulmonary over circulation which was generally associated with normal (> 93%) peripheral oxygen saturation. Subjects with a pulmonary/systemic blood flow ratio < 2.00, a velocity–time integral of blood flow in pulmonary veins < 20.0 cm and peripheral oxygen saturation < 93% were presumed to have heightened pulmonary vascular resistance, thus requiring special attention postoperatively. The tricuspid annular plane systolic excursion (TAPSE) was used to estimate right ventricular systolic function.Patients underwent open cardiac surgery for repair of cardiac lesions. Intraoperatively, they had pulmonary arterial pressure and systemic arterial pressure levels recorded before and after cardiopulmonary bypass (CPB). In our institution, patients who are at risk for postoperative pulmonary hemodynamic disturbances, i.e., those with unrestrictive cardiac communications and preoperative signs of pulmonary hypertension are routinely weaned from CPB on 20 ppm inhaled nitric oxide. A pulmonary arterial catheter was inserted by the surgeon to facilitate hemodynamic monitoring in the intensive care unit. Postoperative analgosedation was performed using fentanyl, midazolan and ketamine singly or in combination. Alternatively, morphine and dexmetomidine were used in combination in subjects with a very stable clinical course. Milrinone, epinephrine and norepinephrine were used as inotropic/vasoactive agents. Postoperatively, patients were kept on inhaled nitric oxide during the entire period of mechanical ventilation, except those in whom ventilation was prolonged for reasons other than pulmonary hypertension.early postoperative PAP/SAP. It was also used to compare groups.Invasive assessment of pulmonary and systemic arterial pressures was carried out for at least 2.5 days postoperatively . Patients with unstable clinical course required longer periods of hemodynamic monitoring. To analyse differences between the study groups  pressure curves were constructed based on data obtained during the first 12 h of intensive care unit stay. In that period, patients were still deeply sedated, stable on mechanical ventilation receiving 20 ppm inhaled nitric oxide, and already free from major post-CPB hemodynamic instabilities. We also computed pulmonary/systemic mean arterial pressure ratio (PAP/SAP) and calculated the mean of first 4 values corresponding to the first 6 h of postoperative monitoring. In the study, this parameter was referred to as Postoperative clinical events related to pulmonary vascular tone instability and acute right/left ventricular dysfunction were recorded. These included: (1) typical pulmonary hypertensive crisis defined as a sustained elevation of pulmonary arterial pressure  with a decline in systemic pressure (≥ 20%) and oxygen desaturation (< 90%); (2) systemic hypotension with a pulmonary/systemic mean arterial pressure ratio in the range of 50–75% requiring frequent changes in the doses of vasoactive-inotropic drugs; (3) prolonged and/or recurrent hemodynamic and respiratory disturbances not promptly responsive to sedation and manual ventilation; and (4) all hemodynamic and respiratory critical instabilities requiring cardiorespiratory resuscitation. Transient elevations of pulmonary arterial pressure, even to suprasystemic levels, that were rapidly reversed by sedation and manual ventilation were not characterized as clinical events. Interpretations were made independently by 3 physicians .After discharge from the hospital patients were followed up for 6 months, and then pulmonary hemodynamics was re-evaluated noninvasively by means of transthoracic echocardiography. An adequate tricuspid regurgitation jet Doppler signal was required to estimate systolic pulmonary arterial pressure. That was not possible in subjects with negligible tricuspid regurgitation. All factors and covariates that were recorded perioperatively were tested for a possible role in predicting post-hospitalization pulmonary arterial pressure.Mycoplasma pneumoniae.Nasopharyngeal and tracheal aspirates were obtained from all patients for detection and identification of respiratory viruses. Nasopharyngeal aspirates were obtained 2–3 days before surgery in the complete absence of respiratory symptoms. Tracheal aspirates were collected in the operating room just after orotracheal intubation. Nucleic acid extraction was performed using the EASYMAG system  according to the manufacturer’s instructions. Samples were subjected to real-time polymerase chain reaction  using the ABI 7500 system . A Multiplex Kit  was used for detection of 19 respiratory pathogens including 18 viruses and Peripheral venous blood was collected 2–3 days before surgery and 4 h after CPB termination for analysis of serum levels of 36 inflammatory mediators. Proteins were analyzed by immunoblotting using a human cytokine array . Samples were processed in duplicate and proteins were semiquantified by chemiluminescence. The results were obtained taking the average signal of each pair of duplicate spots and expressed as units of pixel intensity (upi). Preoperative and postoperative samples were always run in the same assay.Preoperative and postoperative clinical and hemodynamic assessments and laboratory analyses (respiratory viruses and inflammatory mediators) were carried out in a blinded fashion.Unless otherwise specified, numerical data are presented as medians with interquartile ranges. Categorical data are presented as number of cases and percentages. Descriptive statistics was performing using the Mann–Whitney test and the Chi-square family of tests for comparisons between groups. The Wilcoxon test, Friedman’s test and linear regression analysis were used to test for differences and associations within subjects. Inferential statistics was carried out using the General Linear model  to test for differences between groups regarding the behavior of hemodynamic parameters and curves. In this case, the distribution of the dependent variables was tested for closeness to the normal (Gaussian) distribution and when necessary, variables were analyzed after Box–Cox transformation. Predictors of hemodynamic abnormalities and clinical events were identified using univariate, bivariate and multivariate Logistic regression analysis. Once a predictor was identified, a second variable was characterized as a confounder or enhancer if its inclusion in the statistical model resulted in a > 10% change in the original odds ratio. In all tests, 0.05 was set as the significant level. Statistical analysis was performed using the SPSS statistical software, version 28 .r = − 0.34, p = 0.009) further suggesting some degree of right-to-left shunting at baseline. On the other hand, 25% of patients had a pulmonary/systemic blood flow ratio greater than 2.90 which was generally associated with overt pulmonary congestion and failure to thrive. According to information obtained from parents, at least 20% of patients had respiratory viral infections prior to referral to the Heart Institute. Twenty-five patients (41.7%) had episodes of bronchiolitis and 22 (36.7%) had pneumonia requiring hospitalization.A flow diagram showing how patients were selected is shown in Fig. p < 0.001. For pulmonary/systemic mean arterial pressure ratio values were 0.78 (0.63–0.88) and 0.40 (0.33–0.48), respectively, p < 0.001. Postoperatively, 14 patients had relevant clinical events as defined, which contributed to prolonged mechanical ventilation (p < 0.001). One patient died of septicemia. Another patient died in the course of rapid-onset systemic hypotension followed by bradycardia unresponsive to vasopressin and other life-supporting interventions.All patients underwent complete surgical repair of cardiac anomalies. Pre-CPB mean pulmonary arterial pressure and pulmonary/systemic mean arterial pressure ratio were elevated. Both parameters decreased significantly after elimination of cardiac shunts. However, in the majority of patients they remained above optimal guidelines levels of 20 mmHg and 0.30, respectively . Pre- anMycoplasma pneumoniae.It was possible to characterize respiratory viral genomes in nasopharyngeal and tracheal aspirates in 58 and 55 patients, respectively. For the remaining patients, the amount of molecular material present in the aspirates was considered insufficient for analysis. The percentage of patients carrying genetic material for each of the viruses investigated in the study is shown in Fig. p = 0.037).The behavior of pulmonary and systemic arterial pressure and peripheral oxygen saturation during the first 12 h of postoperative care is shown in Fig. p = 0.008. Using univariate analysis, we identified 8 factors potentially correlatable with early postoperative PAP/SAP, with p values < 0.10 (Table p = 0.002) and the presence of viral genomes in the trachea  remained in the multivariate model. The final logistic regression equation was: Ln (p/1 − p) = 1.290 + 1.487* 0 or 1 for absence or presence of viruses − 0.909* baseline oxygen saturation, where p is the probability of having an early postoperative PAP/SAP > 0.40. Because rhinovirus was the most prevalent agent, we analyzed early postoperative PAP/SAP comparatively in patients carrying only rhinovirus (n = 8) and those who were negative for all investigated viruses (n = 34). The respective values were 0.45 (0.33–0.59) and 0.34 (0.30–0.45) (p = 0.041 after adjustment for baseline oxygen saturation). We also analyzed the postoperative behavior of the pulmonary circulation specifically in patients who entered the study prior to SARS-CoV-2 pandemia. Early postoperative PAP/SAP in patients with (n = 17) and without (n = 29) viral genomes in tracheal aspirates was 0.42 (0.36–0.53) and 0.34 (0.29–0.43), respectively, p = 0.007. For patients who entered the study during the pandemia, values were 0.44 (0.36–0.46) (n = 4) and 0.35 (0.30–0.57) (n = 5), respectively.The analysis of factors with possible influence on postoperative hemodynamics in addition to the presence of viral genomes in the trachea was carried out using early postoperative PAP/SAP as dependent variable; values > 0.40 were shown to be associated with relevant postoperative clinical events . In the 10 Table . Howeverr = 0.50, p < 0.001). Besides, there was a marked increase in circulating IL-1RA with negligible changes in IL-1 (spare receptor phenomenon). The relationship between post-CPB inflammatory response and development of postoperative pulmonary hypertension was investigated. Of 36 inflammatory proteins that were analyzed in serum 4 h post CPB, 10 were found to have a possible influence on early postoperative PAP/SAP with p values < 0.10 , while higher levels of post-CPB mean systemic arterial pressure were protective . Importantly, there was a direct relationship between the occurrence of postoperative events and the duration of mechanical ventilation (p < 0.001).Postoperative clinical events were closely related to early postoperative hemodynamics, as shown in Table Fifty-eight individuals were discharged from the hospital and were seen in outpatient medical settings 6 months after operation. In 55 subjects, there was an adequate tricuspid regurgitation jet Doppler signal on 6-month postoperative echocardiogram allowing for the estimation of systolic pulmonary arterial pressure. While analyzing factors and covariates that were recorded perioperatively, we observed that the presence of viral genomes in tracheal aspirates and early postoperative PAP/SAP interactively influenced post-hospitalization levels of pulmonary artery pressure Fig. .Fig. 4InViruses are the leading cause of respiratory disorders and lung cell injury. This is particularly so in the pediatric population –27. In tSome of our patients had respiratory viral infections in their clinical history, others did not. The question might be raised if respiratory viruses remain active in asymptomatic individuals. In addition, because different pathogens were detected in the study population, it would be worth discovering which ones are capable of infecting the distal lung as to cause relevant changes in small airways and eventually vessels. Although these are difficult points to address in the context of the present study, preliminary thoughts can be formulated with regard to rhinovirus, the most prevalent agent in our cohort. Rhinoviruses are known for their chronic behavior in many instances and their ability to alter the biology of peripheral lung cells. Although infections are usually mild and limited to the upper respiratory tract, there is growing evidence that they can induce lower respiratory tract pathology with severe pulmonary and extrapulmonary complications in adults and children , 32. In In our patients, the inflammatory response to surgery under CPB was characterized by an increase in the number of circulating monocytes, a marked increase in neutrophil to lymphocyte ratio, a decrease in platelet count and changes in serum levels of several cytokines and related proteins. The inflammatory reaction seemed to explain the hypertensive postoperative behavior of the pulmonary circulation at least in part. While it is known that multiple mechanisms are involved in pulmonary vasoconstriction and hypertension in acute conditions , it is wWe also investigated factors that have been classically linked to postoperative pulmonary hypertension in this population. While patient’s age (maximum of 35 months in the study) did not seem to influence postoperative pulmonary hemodynamics, the presence of Down syndrome may have played an indirect role via the complexity of cardiac anomaly  with longer surgical times (CPB duration) and presumably, more pronounced inflammatory response. Peripheral oxygen saturation was found to be an important predictor of postoperative hemodynamics. This was probably due to the fact that oxygen saturation reflected the status of the pulmonary circulation at baseline. In fact, bedside oxygen saturation was negatively correlated with pre-CPB pulmonary artery pressure measured directly in the operating room. Although oxygen saturation did not correlate with the presence/absence of viral genomes in the airways, we cannot totally exclude chronic airway abnormalities as a cause for lower-than-normal oxygen saturation levels in some individuals. Upper airway obstructions may have contributed to imbalances between ventilation and perfusion especially in patients with Down syndrome. Bidirectional shunting within the cardiac chambers as a result of heightened pulmonary vascular resistance may also have contributed to systemic oxygen desaturation in some cases.We showed an association between the presence of respiratory viral genomes in the trachea and the hypertensive behavior of the pulmonary circulation in pediatric patients undergoing surgery for congenital cardiac septal defects, thus suggesting a pathophysiological role for respiratory viruses on the development of pulmonary vascular abnormalities. Because we did not investigate if patients were still carriers for viruses after operation (study limitation), we can only speculate that new biological events initiated at the time of surgery involving inflammation and persistence of viral activity might partly explain the hemodynamic alterations that were still present in some individuals after discharge from the hospital. Further research is needed to clarify such relationships.