Most patients with hydrocephalus are still managed with the implantation of a cerebrospinal fluid (CSF) shunt in which the CSF flow is regulated by a differential-pressure valve (DPV). Our aim in this review is to discuss some basic concepts in fluid mechanics that are frequently ignored but that should be understood by neurosurgeons to enable them to choose the most adequate shunt for each patient. We will present data, some of which is not provided by manufacturers, which may help neurosurgeons in selecting the most appropriate shunt. To do so, we focused on the management of patients with idiopathic “normal-pressure hydrocephalus” (iNPH), as one of the most challenging scenarios, in which the combination of optimal technology, patient characteristics, and knowledge of fluid mechanics can significantly modify the surgical results. For a better understanding of the available hardware and its evolution over time, we will have a second look at the design of the first DPV and the reasons why additional devices were incorporated to control for shunt overdrainage and its related complications. We try to persuade the reader that a clear understanding of the physical concepts of the CSF and shunt dynamics is key to understand the pathophysiology of iNPH and to improve its treatment. Hydrocephalus is the most frequent cause of acute and chronic intracranial hypertension both in children and adults and is the condition that pediatric neurosurgeons treat most frequently. Despite the popularity of endoscopic third ventriculostomy in the neurosurgical armamentarium, most patients with hydrocephalus are still managed with the implantation of a cerebrospinal fluid (CSF) shunt in which the CSF flow is regulated by a differential-pressure valve (DPV). The first generation DPVs were introduced in the 1950s and most of the valves designed soon after World War II are still used today, with minor modifications . In the Until recent years, the most complex problem neurosurgeons faced was to choose among a low-, medium- or high-pressure DPV . The widCurrent shunt technology allows for selection among a wide variety of hardware and adapts it to patients’ age, height, weight, clinical, and neuroradiological characteristics. This selection is especially relevant in patients with iNPH in which the shunt selection is essential to reduce both the rate of nonresponders and shunt-related complications. In pediatric neurosurgery, the goal of selecting the most adequate shunt hardware is to reduce the number of shunt-failures that infants and children will have until they become adults, an important factor in obtaining their best long-term outcomes and social integration.Our aim in this review is to discuss some basic concepts in fluid mechanics that are frequently ignored but that should be understood by neurosurgeons to enable them to choose the most adequate shunt for each patient. We present data, some of which is not provided by manufacturers, which may help neurosurgeons in selecting the most appropriate shunt. To do so, we focus on the management of patients with iNPH, as one of the most challenging scenarios, in which the combination of optimal technology, patient characteristics, and knowledge of fluid mechanics can significantly modify the surgical results. Although our statement seems to be contradictory with the lack of evidence that any valve or shunt assembly is superior in managing hydrocephalus , we hopeIn brief, a modern CSF shunt has five major components: (1) a ventricular catheter, (2) a reservoir, (3) a valve system, (4) an antisiphon (ASD)/gravity compensating-device, and (4) a distal catheter ,6. BecauFor a better understanding of the available hardware and its evolution over time, we will have a second look at the design of the first DPV and the reasons why additional devices were incorporated to control for shunt overdrainage and its related complications . We try One of the first attempts in managing hydrocephalus was reported by Dandy who proposed third ventriculostomy to treat obstructive hydrocephalus and the extirpation/coagulation of the choroid plexus in communicating hydrocephalus . Early a2O (2.2 mmHg) [The discovery of the silicone elastomers in 1943 was a significant milestone in medicine. Silicone is an inert material with low interaction with biological tissues that sustains high temperatures and therefore, it can be sterilized . Later, .2 mmHg) . The fir.2 mmHg) .In any nonelastic tube, liquid flow is driven by the pressure difference between the inlet and outlet. This was the remarkable finding that Poiseuille found in the experiments he designed to understand the laws governing blood flow in the microcirculation . Poiseui1 and P2 are the pressures at the inlet and the outlet of the tube, respectively, R is the radius of the tube, η the viscosity of the fluid, L the length of the tube, and π and 8 are constants. The viscosity of CSF is close to the viscosity of water, which is 0.7–1 mPa-s at a temperature of 37 °C [1–P2 and inversely proportional to the resistance of the tube that depends on R, η, and L. However, in any shunt assembly, the distal tube is only a part of a more complex design and therefore the total resistance of the shunt (Rshunt) is always higher than the resistance of the distal catheter.In Equation (1), Pof 37 °C . Q in a 1–P2) is the inlet–outlet differential pressure and Rshunt the total resistance of the shunt assembly. In an electrical circuit in which resistors are connected in series, the total resistance (impedance) will be calculated by adding up the impedance of the individual resistors: R = R1 + R2 + R3 +…. If an electric circuit has three in series resistors with an impedance of 8 Ω, 3 Ω, and 2 Ω respectively, the total impedance of the circuit will be 13 Ω. In a similar way, the total resistance of a shunt (Rshunt) is calculated by adding the resistance of all the individual components in the shunt assembly:To address this issue, the analogy between steady-state electrical current flow in an electric circuit and the flow of an incompressible fluid in a nonelastic tube is helpful. In an electric circuit, the electric flow is defined by Ohm’s law that when applied to fluid dynamics can be restated:shunt is obtained by adding the individual resistances of the ventricular catheter (Rvent), the distal catheter (Rdist), the resistance of the valve , and that of any additional device added in series to compensate for gravitational changes (Rgrav). The normal resistance to CSF outflow (Rout) in healthy individuals ranges from 5 to 10 mmHg/mL/min, and this resistance increases with age [In Equation (3), Rwith age ,17. When1) and outlet pressures (P2) and inversely proportional to the total resistance of the shunt (Rshunt) as defined in Equations (2) and (3).In vitro, the flow across a shunt assembly, as defined in Equation (1), is directly proportional to the driving pressure, which is the difference between the inlet (Pshunt) introduced by Rayport and Reiss [shunt in VA shunts as the algebraic difference between the intraventricular pressure (IVP) and either the closing pressure (CP) of the DPV valve or the atrial pressure, “whichever is larger” [shunt concept by introducing the gravitational-induced hydrostatic pressure (HP) in the algebraic definition (2O (~37–50 mmHg) when a medium-height shunted patient is sitting or standing  is the outlet pressure. An important concept to grasp is that in any DPV, the valve will be always closed when PPshunt is ≤0, and it will open when PPshunt is >0. Once the valve is opened, the CSF flow through the shunt will be regulated by Equation (2).As shown in The definitions provided for opening pressure (OP) and CP in a DPV in many published papers are misleading. Most manufacturers report either the OP or the CP as required by the International Organization for Standardization (ISO), ISO 7197:2006, which regulates the minimum mechanical and technical requirements that manufacturers should report for implants used in the treatment of hydrocephalus . In mostTM “slit n’ spring” valve  is a low-cost shunt in which the slit valve is protected by a stainless steel spring [In any shunt assembly, the valve is the most important component because it regulates when the CSF flow starts and stops and it changes the amount of CSF fluid that passes through the shunt when intracranial pressure (ICP) is high. DPV can be classified according to the mechanical design in slit, miter, diaphragm, or spring-loaded “ball-in-cone” valves . Most ofl spring   and the miniNAV® . Compared to silicone valves, ball-in-cone valves have a more precise OP and sustain higher CSF protein levels before becoming clogged than do silicone valves. Independent studies have shown that, in general, ball-in-cone valves have better mechanical characteristics than silicone valves and show a better convergence of pressure–flow performance when tested in vitro [Spring-loaded ball-in-cone valves use a completely different approach to regulate pressure. These valves incorporate a metallic spring that exerts the manufacturer’s predefined force to a synthetic ruby ball located in a cone-shaped orifice . When thin vitro ,24. Despin vitro , as far All of the silicone-based valves have the viscoelastic properties of the silicone elastomers; therefore, aging of these materials may significantly alter their performance. However, degradation and calcification of silicone catheters with deterioration of their mechanical properties, predisposition to catheter fractures, and migration of the different parts of the shunts have been reported only for catheters that are in direct contact with the subcutaneous tissue  but not ® programmable valve (Integra LifeSciences Corporation). The Codman–Hakim® is one of the best available adjustable valves, but it is also a good example of the limitations of such valves. In the earliest Hakim adjustable valve, the OP could be adjusted to 18 settings in small increments of 10 mmH2O by the application of an external magnetic field [2O (Integra LifeSciences Corporation).Since the early 1990s, most manufacturers have produced both valves with fixed OP and adjustable (“programmable”) valves in which the OP settings can be modified noninvasively. The first available commercial adjustable valve (AV) was patented by Hakim in 1986 ; it is kic field . The mosThere is still a fundamental misunderstanding of the reasons Hakim thought that an AV was required to manage hydrocephalus. AVs were not introduced for controlling shunt overdrainage, which is the wrong strategy for avoiding it, but to modify the OP to normalize the changes that an implanted shunt induces in ventricular size, IVP, and subdural stress ,29,30. IAccording to Hakim’s hypothesis, the part of the IVP that is not absorbed by the brain parenchyma is transmitted to the subdural space and is referred as subdural stress. Its magnitude is directly related to the ventricular size, and Hakim considered it one of the most important factors in hydrocephalus development . In his shunt is >0; however, when patients assume a standing or sitting position, the gravitational-induced HP will overcome the OP even at the highest OP settings (200 mmH2O = 14.7 mmHg). As described by Meier and Kintzel, they will “remain open too long when the patient moves into the upright position. In this way they could induce suction on the already atrophic brain” and therefore expose the iNPH patient to the adverse events induced by shunt overdrainage [Today, most neurosurgeons choose AV in iNPH patients for three main purposes: 1) controlling overdrainage by increasing the OP, (2) reducing the OP when improvement does not occur, and (3) partially closing the shunt to manage subdural effusions. However, as is discussed elsewhere, the use of AV for managing overdrainage is a mistaken strategy and, as Aschoff remarked, users that select it “can select different grades of over-drainage only, but not avoid it” [ controlldrainage . The rea® programmable valves, are sensitive to magnetic fields and therefore require routine reprogramming when an MRI is performed  reduce shunt overdrainage induced by the posture-increase in hydrostatic pressure when patients are standing or sitting ,36. In aDespite the lack of evidence, the guidelines for the treatment of iNPH published in 2005 concluded that “several retrospective studies suggest that adjustable (“programmable”) valves offer an advantage over fixed valves because corrections for under- or overdrainage, which are encountered relatively frequently with iNPH, can be performed noninvasively instead of requiring a surgical revision” . HoweverIn high-income countries, AVs double the cost of a fixed valve from the same manufacturer. However, in low- and medium-income countries, AVs have a significantly higher cost—in some countries, outrageously overpriced—than fixed valves, and therefore AVs are not affordable. However, despite the lack of robust evidence about their benefits, and when cost is not a relevant variable, it is important to take into consideration that AVs allow us to fine-tune the OP in many pediatric and adult patients with hydrocephalus and might reduce the number of shunt revisions.shunt in regulating CSF flow. However, from Equation (2) it is obvious that when the valve in a shunt is opened, CSF flow is regulated by both PPshunt and Rshunt.Up to this point, we discussed how DPV valves open and close and the effect of the PPshunt is never reported by shunt manufacturers, and is available only from independent laboratories typically supported by research grants or academic institutions [Interestingly, Ritutions . In Euroitutions , and in itutions , but theitutions .shunt in the management of hydrocephalus, in 2O (0–44 mmHg). Most manufacturers provide distal catheters with an ID between 1.0 and 1.40 mm for VP/VA shunts, and some LP designs have catheters with an ID of 0.50–0.80 mm. As shown in this figure, following Poiseuille’s law, flow through a constant tube length decreases as internal diameter decreases.For a better understanding of the relevance of Rshunt = 6 mmHg—would be ~209 mL/h. When this shunted patient stands (2O (51 mmHg) when the patient is standing, the CSF flow could increase to a maximum of 1700 mL/h. In this simulated scenario, the patient exceeds the physiological production of CSF . In this situation, the cerebral ventricles will rapidly collapse, and the patient would be exposed to all the complications of shunt overdrainage. If another neurosurgeon had decided to implant a valveless silicone tube of the same length but with an ID of 0.60 mm : 27.4, moderate overweight). ICP monitoring showed a mean ICP of 8 mmHg with ~40% high- and low-amplitude B-waves—wave amplitude > 10 or ≤ 10 mmHg, respectively—compatible with the diagnosis of iNPH . If a net stands , IVP is  0.60 mm , the samBased on this basic hydrodynamic principle, Sotelo, a Mexican neurosurgeon, introduced in 1993 a low-cost valveless shunt for managing patients with hydrocephalus ,50. In tshunt and Rvalve are not provided by most shunt suppliers and they need to be estimated from the flow–pressure data provided (2O (12.8 mmHg) [2O (5.1 mmHg), but the external ventriculostomy was maintained for controlling the CSF output. The patient deteriorated again after surgery, and the CSF outflow at neuroworsening was above 25 mL/h despite a functional shunt. To manage this problem, the girl required a second Pudenz–Heyer shunt implanted in parallel to drain the excessive CSF production that a single shunt was unable to manage [The previous examples reflect the need to consider the resistance of all the components of a shunt assembly and, ideally, to have, at least, good estimates of the IVP and IPP when managing individual patients with iNPH. Rprovided . However.8 mmHg) . In thiso manage .shunt of the three similar medium-pressure DPVs were significantly different: 2.4 mmHg/mL/min for the Cordis–Hakim, 4.2 for the Pudenz–Heyer, and 16.6 mmHg/mL/min for the Spitz–Holter  with the same reported nominal CP range . The preshunt in the literature, raised indirectly by Rayport and Heiss’s seminal paper, was largely neglected in the neurosurgical literature and reassessed only after the studies of independent bodies such as the Aschoff and Cambridge shunt laboratories were published [shunt much lower (<2–5 mm Hg/mL/min) than the normal physiological values quantified by infusion tests, which are in the range 6–10 mmHg/mL/min [The relevance of the Rublished ,52. Czosublished . In theig/mL/min .shunt values of some DPVs with and without the distal catheter attached, using the results reported by the Cambridge Shunt Laboratory in various publications [shunt even with the attached distal catheter, and therefore overdrainage will be induced depending on the variables already discussed. A second message is that different valves included by manufacturers in the same category  have variable OP and significantly different hydrodynamic profiles that should be known when managing difficult cases or reconsidering shunt revision in nonresponsive iNPH patients in which shunt underdrainage is suspected.In ications ,55,56,57Patients with hydrocephalus are a heterogeneous population. In their management, there is a subgroup of complex cases in which an adequate shunt selection and in-series or integrated devices  are much more relevant than in conventional patients to reduce the risk of overdrainage and shunt malfunction, and to improve their outcome. Some cases of pediatric hydrocephalus or iNPH, post-traumatic hydrocephalus and the entity defined by Oi in 1996 named long-standing overt ventriculomegaly in adults (LOVA)  are someMost of these complex patients share a significant increase in ventricular size (I. Evans > 0.42) and a significant disproportion between the intracranial and the cerebral volume—with or without macrocephaly. In these patients, ICP monitoring has shown different profiles, but, frequently, these patients have a mean ICP < 12 mmHg . Oi et aHowever, in treating LOVA or LOVA-like patients, we support the idea of Kiefer et al. that for these patients the best treatment option is the combination of an AV with a gravitational device . In theiIt is obvious that any DPV is unable to control for shunt overdrainage when implanted without any gravitational-control or antisiphon device in patients without a significant increase in the IPP. This topic is discussed in another part of this Special Issue. However, devices to control for postural-induced changes in hydrostatic pressure are not yet generally used in adult and pediatric neurosurgery.To close this review, we would like to give some recommendations for selecting the most appropriate shunt for a patient with iNPH. The reader needs to take into consideration that our recommendations are not evidence-based because of the lack of controlled trials and that they are exclusively based on the quantitative assessment of CSF dynamics and the reports elaborated from independent bodies regarding valves and shunts. We have also incorporated the experience of the senior authors in monitoring many patients with iNPH before and after shunting ,66. AlthIn patients with iNPH and unknown IVP, because ICP is not available or used, it is recommended to use low-pressure valves. The use of these valves will avoid problems with underdrainage when the patient is recumbent. Selecting high-pressure DPVs does not control overdrainage and increases the risk of underdrainage while the patient is recumbent.Spring-and-ball mechanical valves are much more reliable in OP than are silicone-based valves. In shunt to be reduced when the patient is standing. Therefore, neurosurgeons should consider gravitational control—either integrated in the valve or as an added device—in most patients in which DPVs are used. As Czosnyka et al. cautioned, neurosurgeons should take care when implanting “low-resistance shunts” into patients with gross ventricular dilatation or greatly increased cerebrospinal compliance, and of their subsequent mobilization, if no siphon control mechanism is added [Without gravitational control of the postural-induced hydrostatic pressure, all DPVs, independent of their OP, will overdrain when the patients assume the standing or sitting position. An exception to this rule is when for different reasons—obesity, pregnancy, abdominal distension, etc.—IPP is significantly raised, causing PPis added .In the selection of DPVs, we recommend knowing the specifications provided by the manufacturer and the hydrodynamic properties of the selected shunt from independent research. It is important to remember that a high resistance valve together with a catheter of reduced ID increases the risk of nonresponse in iNPH patients.shunt. Apart from height, weight, and BMI, an estimation of the mean ICP and IPP is helpful [The most rational approach to selecting the most appropriate shunt for an individual patient is to have the best information concerning shunt hardware and as many patient variables as possible that will influence PP helpful .In low- and medium-income countries, AVs are significantly overpriced and therefore not affordable. However, despite the lack of robust evidence about their clinical benefits, and when cost is not a relevant variable, AVs allow us to fine-tune the OP in many pediatric and adult patients with hydrocephalus and might reduce the number of shunt revisions.Shunt Book published by Drake and Sainte-Rose: “Even if the ideal shunt existed, it would be quickly rendered useless by improper surgical technique during implantation” [An important recommendation for all neurosurgeons involved in the management of iNPH was introduced in the ntation” .


Background: This study aims to investigate the association between blood pressure (BP) at the time of recanalization and hemorrhagic transformation in large vessel occlusion (LVO) patients following mechanical thrombectomy (MT) with general anesthesia.Methods: We retrospectively reviewed our data base for patients with acute ischemic stroke acute ischemic stroke (AIS) who received MT between January 2018 and December 2019. The BP at two adjacent time points immediately after successful recanalization was recorded for subsequent calculation of mean BP (BPmean), maximum BP (BPmax), minimum BP (BPmin), range of BP (BPrange), and standard deviation of SP (BPSD). Hemorrhagic transformation was identified on 24-h computerized tomography images according to the European Cooperative Acute Stroke Study (ECASS) III trial. We used binary logistic regression analysis to investigate the association of BP parameters and the incidence of parenchymal hemorrhage (PH) and PH-2.Results: A total of 124 patients with anterior circulation LVO were finally included for analyses. After controlling for intravenous thrombolysis, procedure duration of mechanical thrombectomy, baseline National institutes of Health Stroke Scale (NIHSS), baseline ASPECTS, and number of device passes, the results showed that every increment of 10 mmHg in SBPrange  and SBPSD  were independently associated with PH. After adjustment for intravenous thrombolysis, procedure duration of mechanical thrombectomy, baseline NIHSS, the results showed that every increment of 10 mmHg in SBPmean , SBPmax , SBPrange  and SBPSD  were independently associated with PH-2.Conclusion: Patients with higher systolic BP and variability at the time of successful recanalization were more likely to have PH-2 in LVO patients following MT with general anesthesia. Mechanical thrombectomy (MT) for large vessel occlusion (LVO) has proved to be the new standard of therapy in acute ischemic stroke (AIS) . But morSeveral studies have shown that blood pressure after MT is related to hemorrhagic transformation. Goyal et al. have found that elevated maximum systolic BP levels during the first 24 h following MT are independently correlated with worse functional outcomes in LVO patients . AnotherIn light of these considerations, we aimed to investigate the relationship between BP at the time of recanalization and hemorrhagic transformation and hypothesized that patients with elevated BP had higher risk of hemorrhagic transformation.MT under general anesthesia is our center's first choice standard procedure. Only in a few cases when the anesthesiologist could not arrive at the angio-suite in time is MT under conscious sedation chosen. Considering the difference of BP levels between patients under general anesthesia and conscious sedation, we excluded patients with conscious sedation in order to reduce the heterogeneity of study subjects. Propofol, sufentanil, and rocuronium were used to induce general anesthesia. Propofol was used for the maintenance of anesthesia. The BP control target in our center is to maintain BP at ≤ 180/105 mmHg during the MT procedure in patients who undergo mechanical thrombectomy. During the operation, BP can be regulated by using vasoactive drugs.We retrospectively reviewed our data base for LVO patients who received MT from January 2018 to December 2019. This study included patients who (1) had internal carotid artery or middle cerebral artery occlusion, (2) received MT with general anesthesia, (3) achieved thrombolysis in myocardial infarction (TICI) 2b/3 recanalization after the procedure, and (4) had 24–36 h follow-up CT scan for evaluation of hemorrhagic transformation. Patients who had baseline systolic BP (SBP) ≥200 mmHg were excluded before the initial inclusion stage.We retrieved data including age, gender, baseline National Institutes of Health Stroke Scale (NIHSS) score, baseline systolic BP (SBP), and diastolic BP (DBP) levels, vascular risk factors including atrial fibrillation, diabetes mellitus, hypertension, hyperlipidemia, smoking, and history of stroke/transient ischemic attack (TIA), time from onset to successful recanalization—which was defined by TICI scores of 2b or 3 after M  number oContinuous arterial BP during the mechanical thrombectomy was automatically monitored by invasive BP monitoring using an arterial catheter in patients under general anesthesia. BP values were recorded every 15 min. Blood pressure at two adjacent time points immediately after successful recanalization was recorded for subsequent calculation. The maximum (max), minimum (min), average (mean), range (maximum–minimum), and standard deviation (SD) values of BP at the time of successful recanalization were calculated.t-test, or Mann-Whitney U-test for continuous variables. Associations of each BP parameter with PH was determined using binary logistic regression models adjusted by baseline characteristics with a P < 0.1 in univariate analyses and some well-recognized confounders, respectively. The receiver operating characteristic (ROC) derived optimal cutoff was determined at the maximal Youden's Index. All statistical analyses were performed using SPSS, Version 23.0 . A P < 0.05 was considered statistically significant.Quantitative variables were presented as mean ± SD or median (interquartile range)—depending on the normality of the distribution—and categorical variables were presented as frequency (percentage). We use Fisher's exact test for dichotomous variables, an independent sample 2-tailed n = 20), conscious sedation (n = 26), and no 24–36 h follow-up CT scan (n = 7).Initially, 177 patients with occlusion of the internal carotid artery or middle cerebral artery treated with MT were included. As shown in Of the 124 analyzed patients, the mean age was 66 ± 12 years, and the median baseline NIHSS score was 15 (IQR 11–18) For this group, mean onset-to-reperfusion time was 415 (IQR 317–540) min. A total of 18 (14.5%) had PH at 24–36 h, and 10 of them were PH-2 (8.1%).P = 0.009), a higher number of device passes, smaller baseline ASPECTS , higher 24 h NIHSS , and lower rate of 3 months mRS ≤ 2  than those without PH. The SBPmax (P = 0.046), SBPrange (P = 0.037), and SBPSD (P = 0.037) were higher in the PH group. There were no significant differences in other variables, including baseline BP. After controlling for intravenous thrombolysis, procedure duration of mechanical thrombectomy, baseline NIHSS, baseline ASPECTS, and the number of device passes, the results showed that every increment of 10 mmHg in SBPrange  and SBPSD  were independently associated with PH (As shown in  with PH .P = 0.005), higher 24-h NIHSS , and lower rate of 3 months mRS ≤ 2  than those without PH-2. The SBPmax (P < 0.001), SBPmean (P = 0.001), SBPrange (P = 0.001), SBPSD (P = 0.002), DBPmax (P = 0.006), SBPmean (P = 0.001), SBPmin (P = 0.046) were higher in the PH-2 group. After adjustment for intravenous thrombolysis, procedure duration of mechanical thrombectomy, and baseline NIHSS, the results showed that every increment of 10 mmHg in SBPmean , SBPmax , SBPrange  and SBPSD  were independently associated with PH-2 (Patients with PH-2 had a higher baseline NIHSS score (18 vs. 14, ith PH-2 .mean, SBPmax, SBPrange, and SBPSD in predicting PH-2 are shown in mean, SBPmax, SBPrange, and SBPSD, respectively (mean, SBPmax, SBPrange, and SBPSD. As shown in max.The ROC curves of SBPectively . Table 3mean/SBPmax, and higher BP variability measured by SBPrange/SBPSD at the time of successful recanalization were consistently associated with a higher likelihood of PH-2 in LVO patients following MT with general anesthesia.Our data suggest that higher systolic BP, measured by SBPmean and SBPmax at the time of successful recanalization after MT with general anesthesia were associated with a higher risk of PH-2. Potential reperfusion injury to ischemic tissue may explain why PH-2 was more common in those patients who had higher SBP after MT. Cerebral perfusion pressure is linearly correlated with BP due to impaired cerebral autoregulation following ischemia (The recommendations of the American Heart Association/American Stroke Association guidelines for BP control in LVO patients treated with MT indicate that an optimal BP target that simultaneously avoids the risk of hemorrhagic transformation and impairment of cerebral perfusion remains unknown . Avoidinischemia . The incischemia .range/SBPSD at the time of successful recanalization were prone to have PH-2, which is consistent with other related studies. Previous studies had found that blood pressure variability, reflecting the extent of blood pressure fluctuations, could predict unfavorable outcomes in AIS patients receiving intravenous rt-PA (Our study also found that patients with high BP variability measured by SBPus rt-PA . Anotherus rt-PA . Increasus rt-PA , 19. TheThe major difference between our study and other previous studies is that the observation index we focused on is the BP at the time of successful recanalization. Successful recanalization following MT basically solves the risk of hypoperfusion, avoiding reperfusion injury to reduce hemorrhagic transformation becoming more important. Our study suggests that BP has already affected hemorrhagic transformation at the time of successful recanalization in the angio-suite. It may be reasonable to keep BP to low levels and decrease fluctuations since the time of successful recanalization following MT. Interestingly, in line with a previous study , minimalLimitations include the small sample size of the study and its retrospective design, which might have potential for selection bias. Second, we only recorded BP values every 15 min after successful recanalization. It would be more informative to record blood pressure every 3 min or even every minute. Third, we assessed only the relationship between BP and hemorrhagic transformation in AIS patients with anterior circulation LVO occlusion. Therefore, the conclusion can't be simply extended to patients with posterior circulation LVO. Finally, because of limitations of the observational design, the causal relationship between hemorrhagic transformation and blood pressure cannot be determined and prospective randomized controlled trials are needed to address this problem.In conclusion, patients with higher systolic BP and variability at the time of successful recanalization were more likely to have PH-2 in LVO patients following MT with general anesthesia. Further research is needed to confirm this relationship and the optimal treatment target of blood pressure control after MT.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.The studies involving human participants were reviewed and approved by the human ethics committee of The Sir Run Run Shaw Hospital Affiliated with Zhejiang University approved the protocol of this study. The patients/participants provided their written informed consent to participate in this study.HC and CX conducted the statistical analyses and drafted and revised the manuscript. XJ, YC, XZ, FS, XH, YH, and YJ participated in data acquisition and interpretation. ZC and JZ participated in study concept and design, data interpretation and made a major contribution to revising the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The correct tests are as follows: “χ2 analysis was conducted to compare the distributions of categorical variables  between asymptomatic and symptomatic patients. Continuous variables  were compared using t tests.” The findings have been corrected in the Table and are similar to the originally reported comparisons, and the statistical results continue to indicate P < .01. This article has been corrected.The Research Letter, “Comparison of Clinical Characteristics of Patients with Asymptomatic vs Symptomatic Coronavirus Disease 2019 in Wuhan, China,”


Background: Intravenous thrombolysis (IVT) therapy is currently one of the best medical treatments available for patients with acute ischemic stroke. Studies have shown that blood pressure (BP) changes in patients treated with IVT are significantly correlated with prognosis.Objective: Our study aimed to determine the relationship between BP changes during recombinant tissue plasminogen activator (rt-PA) infusion and the 3-month prognosis evaluated using the modified Rankin Scale (mRS) and determine the factors influencing BP changes during rt-PA infusion.Methods: Consecutive patients who were treated with IVT and admitted to our stroke center between May 2015 and October 2017 were analyzed retrospectively. Patients were divided into two groups according to their 3-month prognosis status: patients with mRS ≤ 2 were defined as “favorable outcome group” and those with mRS ≥ 3 as “unfavorable outcome group”. First, the factors affecting prognosis after thrombolysis were analyzed. Second, we analyzed the relationship between BP and the prognosis. BP was taken before and at regular intervals of 15 min during the rt-PA infusion (1 h). The average value of BP during thrombolysis was calculated and compared to the baseline BP. BP decrease was defined as the difference between the baseline BP and the average BP, provided it was greater than 0 mmHg. Third, univariate and multivariate analyses were performed to identify factors that may contribute to BP decrease.Results: In total, 458 patients were included. Patients with a lower baseline National Institute of Health Stroke Scale (NIHSS) score , a higher Alberta Stroke Program Early CT Score , decreased BP during thrombolysis , and steady BP (SD < 10 mmHg) were more likely to have a favorable outcome . High baseline BP (OR > 1), hypertension history (OR < 1), and baseline ASPECTS (OR > 1) were independent factors of BP change during thrombolysis.Conclusion: Patients with decreased or steady BP during thrombolysis were more likely to have a favorable outcome. Baseline ASPECTS, baseline NIHSS score, and hypertension history influenced BP changes during thrombolysis. Stroke is the leading cause of death in the Chinese population because of its high rate of morbidity, disability, mortality, and recurrence, and it negatively affects the national health and quality of life  response to acute ischemic stroke has a high rate of incidence, certain self-limitations, and an effect on prognosis  infusion and 3-month prognosis evaluated using the modified Rankin Scale (mRS) and determine the factors influencing BP during the infusion to better understand this disease and improve its clinical management.Patients who were treated with IVT and admitted to the stroke center of the First Hospital of Jilin University from May 2015 to October 2017 were analyzed retrospectively. IVT was performed within 4.5 h from onset according to current guideline recommendations and the physician’s decision . Because several previous studies have demonstrated that there is a stronger predictive function of systolic BP (SBP) than diastolic BP in patients with ischemic stroke  was evaluated using brain computed tomography (CT). CT examinations were repeated 24 h after thrombolysis. Hemorrhage transformation was evaluated using the 24 h CT scans, following the Second European Cooperative Acute Stroke Study (ECASS-II) classification.mRS was evaluated at the 3-month double-blind follow-up after IVT. Doctors who had recorded the cases were not assigned to follow-up. Detailed addresses and phone numbers were documented on admission to the hospital. Patients with mRS ≤ 2 were included in the “favorable outcome group” and those with mRS ≥ 3 into the “unfavorable outcome group.”t-test. Classified variables were analyzed using the Pearson chi-square test. P < 0.05 was considered statistically significant. A bivariate logistic regression model was used to verify independent 3-month prognostic factors of cerebral infarction and factors influencing BP. Variables with P < 0.1 were included in the multivariate analysis model. Also, a history of atrial fibrillation, coronary heart disease, and hypertension may be potentially correlated with acute BP changes; thus, they were added to the above model.The statistical program for social sciences version 20.0  was used to analyze all data. Continuous variables were expressed as mean (± SD) and were analyzed using a In total, 488 consecutive patients diagnosed with acute ischemic stroke who underwent IVT were screened. Thirty patients who did not meet BP standards or whose laboratory or follow-up data were unavailable were excluded from this study. Finally, 458 patients were included in the study.P < 0.001) and HDL  were significantly lower, whereas the CT ASPECTS  was higher in the favorable outcomes group. Additionally, patients with favorable outcomes were more likely to have decreased BP during thrombolysis . The history of hypertension was significant  in the unfavorable outcome group. Rates of hemorrhage transformation after IVT were significantly different between the two groups . BP decrease developed less hemorrhage transformation . Other factors, such as sex, age, cerebral infarction/TIA history, diabetes mellitus, and other common risk factors, did not show a significant effect on prognosis  score  between the two groups. The 3-month mRS score was lower in the BP decreasing group . Simultaneously, the improvement was more significant  and the rate of favorable outcome (mRS ≤ 2) was higher  in the BP decreasing group. There was no significant difference in fatality rates between the two groups  according to the features of BP during the rt-PA infusion process. There was no significant difference in baseline mRS score . For the BP decreasing group, the better prognosis was correlated with BP SD < 10 mmHg  but not with the range of decrease (P = 0.235 and P = 0.705). For the BP no decreasing group, poor prognosis was correlated with large fluctuations in BP  and a history of hypertension  were more likely to have a decrease in BP during thrombolysis. Baseline CT ASPECTS also significantly influenced BP .Univariate analysis of BP changes involved age, baseline BP, baseline NIHSS score, baseline ASPECTS, and medical history. Univariate analysis showed that patients with a higher baseline BP  and diseases that may affect BP were included in the multivariate analysis. It was noted that baseline BP, history of hypertension, baseline ASPECTS were all independent factors associated with the changes in BP. Patients whose baseline BP  and baseline CT ASPECTS  were higher were more likely to have a decrease in BP during thrombolysis. Additionally, the presence of hypertension also increased the chances of BP decrease during thrombolysis  also influences the prognosis of IVT (Aslanyan et al., High baseline BP and ASPECTS are more likely to cause BP to decrease, while hypertension history is less likely to cause BP to decrease. BP elevation may compensate for the reperfusion of the penumbra. When the average BP varies between 60 and 150 mmHg, capillary capacity can be regulated by constriction and dilation according to BP changes to maintain steady cerebral perfusion (Paulson et al., There are some limitations to our study. First, we excluded patients treated with antihypertensive agents before IVT; thus, we cannot use these findings to guide their BP control. Since we need guidance for BP control in all IVT patients, trials including patients treated with antihypertensive agents are warranted. Second, the study is based out of a single center, and the sample size is limited. Multi-center prospective trials are needed to obtain more reliable results.Patients with a decreased and steady BP during thrombolysis were more likely to have a favorable outcome. Baseline CT ASPECTS, baseline NIHSS score, and hypertension history were independent factors related to BP change. These findings could help predict the prognosis of patients treated with IVT and suggest that BP control during IVT might improve clinical outcomes.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 the Human Ethics and Research Ethic committees of the First Hospital of Jilin University. The patients/participants provided their written informed consent to participate in this study.ZW and CW conceived and designed the study, acquired the data, and drafted and revised the manuscript. All authors analyzed and interpreted the data and critically revised the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Damage to the endothelial glycocalyx is an early indicator of vascular damage and a potential marker of endothelial dysfunction. This study aimed to assess the relationship between markers of glycocalyx damage, endothelial dysfunction, and uraemic toxins in patients with chronic kidney disease.Healthy controls, CKD patients, dialysis patients, and kidney transplant recipients had biochemical markers of glycocalyx damage , endothelial dysfunction , and uraemic toxins (indoxyl sulphate and p-cresyl sulphate) measured. In addition, Sidestream Darkfield imaging was performed using the novel GlycoCheck™ device to measure glycocalyx width by the perfused boundary region (PBR) in the sublingual microcirculation.n = 33), followed by CKD patients (n = 32) and kidney transplant recipients (n = 30) compared to controls (n = 30): hyaluronan: 137 (16-1414), 79 (11–257), 57 (14–218) and 23 (8-116) ng/mL, respectively, p < 0.0001; syndecan-1: 81 (40–529), 46 (21–134), 39 (23–72), and 30 (12–138) ng/mL, respectively, p < 0.0001. Markers of endothelial dysfunction followed a similar pattern. No difference in the width of the PBR was detected between these groups . Glycocalyx damage correlated with markers of endothelial dysfunction  and levels of uraemic toxins .Serum markers of glycocalyx damage were highest in the dialysis group (Levels of biochemical markers of glycocalyx and endothelial cell damage are highest in patients receiving dialysis. Glycocalyx and endothelial damage markers correlated with each other, and with uraemic toxins. Although we could not demonstrate a change in PBR, the biochemical markers suggest that glycocalyx damage is most marked in patients with higher levels of uraemic toxins. Patients with chronic kidney disease (CKD) have an increased morbidity and mortality from cardiovascular disease. There are many contributory factors, however one postulated pathophysiological mechanism is endothelial dysfunction . The preThe glycocalyx has been difficult to study as it is easily damaged during vessel handling and techniques used for invasive animal studies are inappropriate for human use. However, elevated serum concentrations of glycocalyx constituents can be measured and correlate with glycocalyx damage . The devIn vivo rat studies have also demonstrated increased heparan sulphate shedding in tissues exposed to IS [Damage to the glycocalyx appears to be in proportion with kidney dysfunction. Shed markers are incrementally higher across different CKD stages , 13 and ed to IS . TherefoThis study was approved by the ethics committee at Eastern Health  and written informed consent was obtained from all subjects.2), dialysis-dependent patients , and patients with stable kidney transplants through Eastern Health nephrology clinics and dialysis centres. Patients with known haematological disorders, acute or chronic infections, malignancy and pregnancy were excluded. A control group consisted of healthy volunteers with no known significant or ongoing medical issues, not on medications and with normal kidney function, recruited through advertisement fliers distributed throughout the health service.We prospectively recruited patients with CKD . Blood samples from haemodialysis patients were obtained pre-dialysis during the midweek session from the arterio-venous fistula or a tunneled dialysis catheter.Using enzyme-linked immunosorbent assays, we measured serum hyaluronan  and syndecan-1  as markers of the glycocalyx, and serum von Willebrand Factor (vWF),  and vascular cell adhesion molecule (VCAM-1),  as markers of endothelial dysfunction. All measures were performed in duplicate.Analyses to quantify indoxyl sulphate (IS) and p-cresyl sulphate (PCS) were performed as previously described by Calaf et al , with miVisualisation of the sublingual microvessels was performed using Sidestream Darkfield imaging  and the acquired images were analysed using GlycoCheck™ . In brief, a handheld camera is placed sublingually which, using light-emitting diodes, detects haemoglobin travelling through the microcirculation. The software identifies all measurable microscopic vessels and divides them into 10 µm segments to calculate the transit width of the erythrocyte column. It continues recording until 3000 segments are captured. Measurement of the lateral movement of red blood cells into the glycocalyx region gives the perfused boundary region (PBR). A damaged glycocalyx will allow red blood cells to penetrate further towards the endothelium, thus giving a higher PBR (µm) .To reduce inter-operator bias, all GlycoCheck™ readings were performed by a single operator (HL). To assess intra-operator bias, 6 volunteers had three successive measurements of their PBR taken daily over 4 consecutive days, giving a coefficient of variation of 9.56%.Nieuwdorp et al. have previously determined that a sample size of 17 was required to detect a 0.2 µm change in glycocalyx width with 80% power and two-sided alpha of 0.05 between groups . TherefoUnivariate and multivariate regression analyses were used to identify predictors of markers of glycocalyx damage. Hyaluronan and syndecan-1 were used as dependent covariates and natural logarithm transformed because of their skewed distribution. Variables assessed for inclusion in the final multivariate regression model included age, gender, diabetes, systolic blood pressure, body mass index (BMI), patient group, eGFR , p-cresyl sulphate, and indoxyl sulphate.p-value of < 0.05 was considered statistically significant, except for the correlation tests, where the significance level was reduced using the conservative Bonferroni correction to 0.05/10 = 0.005, reflecting that there were 10 such tests. Figures were prepared using R.In each regression model, we fitted large models and then performed stepwise (forward and backward) variable selection with AIC (Akaike’s Information Criterion) as the criterion. The model with minimum AIC was chosen. For simplicity we report only the final model in each case. Data analyses were performed using SPSS  and Stata version 15.1  and R version 3.6 . A n = 2). Demographic, clinical and biochemical characteristics of the patients and healthy volunteers are outlined in Table We recruited 30 healthy volunteers, 32 patients with CKD, 33 dialysis patients, and 30 patients with a kidney transplant. We excluded patients who were microcytic, polycythaemic, unable to be venepunctured or unable to have a sublingual assessment performed. Healthy volunteers who were deemed to be hypertensive or overweight at recruitment were also excluded (p < 0.0001). vWF and VCAM-1 levels were similarly elevated, p < 0.0001 , and log-VCAM-1 and log-vWF correlated with each other . Log-hyaluronan correlated with log-VCAM-1 , log-vWF , and log-uACR . Log-syndecan-1 correlated with log-VCAM-1 , log-vWF , and log-uACR . , and with glycocalyx markers  . The p-values for testing each coefficient are all < 0.001, so all the correlations are significantly different from 0 after Bonferroni correction.Log-IS and log-PCS correlated with each other  and age . When SBP was added to the model including patient group and age, it did not explain extra variance (LR p = 0.09). Although the association of log-IS was strong on its own, this was attenuated when adjusted for patient group  and therefore included in the final model, which determined that only age and group were significantly associated with log-hyaluronan, R2 = 0.50 , SBP, diabetes, BMI, patient group, log-IS and log-PCS were associated with log-hyaluronan. Age, patient group, and log-IS demonstrated the strongest influence based on the highest Res Table . Patient50 Table . Additio2 = 0.41). Inclusion of log-IS in the model with ‘patient group’ attenuated the association of log-IS with log-syndecan-1 . Therefore, the best model for syndecan-1 included ‘patient group’ only  [Assessment of the glycocalyx using kidneys) –36. Studkidneys) . Howeverkidneys) . Other skidneys) .in vivo studies involved manual calculations of the difference between a vessel’s width before and after the passage of a leukocyte at a single reference point. This process is time-consuming and subject to bias. The GlycoCheck™ software bypasses this by performing fully-automated calculations and estimates glycocalyx width based on vessel perfusion and erythrocyte movement. As previously mentioned, this tool has been used in the research of different clinical scenarios. However, unlike other studies, we were unable to detect a difference in the PBR between the different groups of our study. First, this may be due to the cohort of patients recruited in this study. Positive studies using the GlycoCheck™ have assessed the very ill—such as those with sepsis, admitted to the intensive care unit, or undergoing cardiac bypass surgery; [Previously, estimating the glycocalyx with surgery; , 41 wherSecond, there were only a small number of participants recruited. Sample size calculations based on other studies using the same statistical power and significance also suggest a sample size of 12 to 26 per group , 42. DesThere are other potential confounders of the PBR that have not yet been investigated. For example, the effect of vasodilation and vasoconstriction on the calculation of the PBR has not been clarified. This is important in the context of endothelial dysfunction where there is impaired nitric oxide availability and defective vasodilation. Another consideration is the unknown impact of erythrocyte shape, size and quantity on how the PBR is calculated. Participants with known haematological disorders were excluded from this study as PBR measurement may be affected, though this is unproven. Furthermore, the effect of food intake on the glycocalyx and PBR has not been investigated. Blood samples in this study were obtained in a fasting state, as did one study , but notr=-0.47, p < 0.001), whereas serum syndecan-1 did not . In univariate regression analyses, eGFR was associated with both log-hyaluronan and log-syndecan-1 and ‘patient group’ was a significant predictor in multivariable regression, suggesting reduced excretion when renal function is impaired. Of note, both hyaluronan and syndecan-1 are measurable in the urine in health and in disease, [We elected to use syndecan-1 and hyaluronan as markers of the glycocalyx as they represent different structural components of the glycocalyx. However, they are not specific to the glycocalyx. Hyaluronan is present on connective and skin tissues,  whereas disease, , 51 but Our CKD cohort was significantly older than the other participants in this study. Relatively little has been published about how the glycocalyx is affected by age in humans. One study has shown a greater PBR in older humans,  whereas in vivo or in vitro effects of uraemic toxins on the glycocalyx will increase our understanding of the role of the glycocalyx in protecting the cardiovascular health of patients with CKD, thus potentially paving a way for novel therapeutic strategies.This study demonstrates an association between the biochemical markers of glycocalyx damage and the presence of uraemic toxins in patients with CKD. Future studies to determine the metabolism of the glycocalyx, how its serum markers are affected by renal clearance and direct