Therefore, the monitoring and management of renal function is an intrinsic part of comprehensive care in SCD. Management of nephropathy in SCD can be accomplished with SCD-directed therapies and/or CKD-directed therapies. In the past 5 years, novel disease-modifying and palliative therapies have been approved in SCD to target aspects of the disease, such as anemia, inflammation, and vasculopathy. Along with conventional hydroxyurea and chronic transfusion, l-glutamine, crizanlizumab, and voxelotor have all been shown to mitigate some adverse effect of SCD, and their effect on nephropathy is being investigated. CKD-directed therapies such as renin–angiotensin–aldosterone system blockers have long been used in SCD nephropathy; however, more complete long-term studies on benefits are needed. Given the effect of renal disease on survival, further assessment of the mechanisms and efficacy of these SCD-directed or CKD-directed therapeutic agents is essential.The underlying mechanisms of disease in sickle cell disease (SCD) contribute to a multifaceted nephropathy, commonly manifested as albuminuria. In severe SCD genotypes ( Deoxygenated HbS (deoxy-HbS) polymerizes, resulting in fragile red blood cells (RBCs), chronic hemolysis with anemia and inflammation, vasculopathy, intermittent vaso-occlusive episodes (VOEs), and ultimately chronic multiorgan damage.2 In the more clinically severe SCA , a multiorgan vasculopathy predominates and carries an increased risk of premature death.3 Advances in pediatric care in the United States48 has shifted the burden of disease to this new population of young adults with SCD who face a shorter lifespan compared with the general population.10 In this population, kidney disease is prevalent and can progress to CKD which affects mortality. The goal of this review is to discuss advances in SCD-focused therapies and their efficacy in reversing or slowing progression of CKD. In addition, we will describe the role of specific CKD-directed therapies in sickle nephropathy.Sickle cell disease (SCD) is a highly prevalent inherited blood disorder worldwide occurring in 300,000 births annually.1113 in the kidney  with resultant vasculopathy.2022 In addition, free hemoglobin in the proximal tubules likely reduces albumin reabsorption contributing to proteinuria.23 Studies show that iron deposition in the tubular epithelium2426 in SCA are consistent with hemolysis, not chronic transfusion, as the proximate cause of this insult. Cellular damage to the proximal and distal convoluted tubules has been described, and there is a clinical association between hemolysis and albuminuria in this population.28In the glomerulus, there is evidence for endothelial injury in the arterioles and glomerular hyperfiltration, believed to be stimulated by anemia, vasodilation, and medullary ischemia.29 Albuminuria, generally accepted as an early indicator of glomerular injury, can be seen in up to 30% of children and 60% of adults with HbSS, and associates with increasing age.31 In a longitudinal, prospective multicenter study with children and adults, albuminuria at >100 mg/g creatinine was associated with a significantly increased risk of persistent albuminuria and a faster rate of decline in eGFR.32 Persistence of albuminuria predicts the risk of progression of renal disease; thus, early detection of albuminuria and initiation of therapy to halt progression is the general approach to managing sickle cell nephropathy. Genetic modifiers that decrease risk of progression to CKD include higher fetal hemoglobin levels and coinherited α-thalassemia deletions which have net effect of decreasing the sickling effect of HbS. Genetic modifiers that increase the risk of progression to CKD include variants in MYH9, APOL1, and HMOX1.3335 Of note, albuminuria and CKD are common in variant SCD, with or without concomitant diabetes, hypertension, or other glomerulopathy.31 Before determining that a patient has SCD-related kidney disease, clinicians should exclude other potential causes of non–sickle cell–related kidney disease in people with SCD.Sickle cell nephropathy can therefore appear as glomerular hyperfiltration, albuminuria, FSGS, impaired urinary concentration ability (hyposthenuria), metabolic acidosis, hematuria, papillary necrosis, and/or CKD (defined as depressed eGFR and/or proteinuria).3639 and was present in 12% of an observational cohort (N=1056) of people living with SCA, with a mean age of onset of 37 years. In this cohort, most deaths (73.3%) occurred in people with prior organ damage, and renal failure was present in nearly one-third (29.4%) of those patients; CKD predicted death with an adjusted odds ratio (OR) of 2.04 .40CKD is a significant predictor of risk of death in patients with SCD41 Hydroxyurea is a ribonucleotide reductase inhibitor that exerts its effect through multiple mechanisms, including increasing expression of fetal hemoglobin, reducing white blood cell and platelet counts, and increasing NO levels.42 Cumulatively, hydroxyurea decreases RBC sickling, thereby likely reducing downstream endothelial injury, intravascular hemolysis, and depletion of endogenous NO. Hydroxyurea use has been associated with reduced frequency of acute chest syndrome, reduced need for blood transfusions, likely improved mortality,44 decreased prevalence, and/or improvement of albuminuria.4548 A prospective study exploring the efficacy of hydroxyurea and angiotensin-converting enzyme inhibitors (ACEi) in 191 children with SCA, after a mean follow-up of 2.19 years, showed normalization of microalbuminuria in 44% of patients on hydroxyurea. In that study, 16 of 17 hydroxyurea-treated patients without microalbuminuria at the start of the study remained albuminuria-free throughout.49 Another cross-sectional study of albuminuria in 149 adults with SCD found a lower prevalence of albuminuria among patients on hydroxyurea; multivariate analyses showed hydroxyurea was associated with a lower likelihood of albuminuria .50 However, smaller shorter observational studies have not always noted significant benefit.52Hydroxyurea, the cornerstone of disease-modifying therapy in SCA, was approved by the US Food and Drug Administration (FDA) in 1998, initially for the indication of reducing frequency of painful VOEs in SCA.53 The Pediatric Hydroxyurea Phase III Clinical Trial,54 a multicenter, phase III placebo-controlled study of 193 children with SCA, did not identify significant differences in eGFR between the two groups. However, they did note improve urine concentrating capacity in hydroxyurea-treated children, perhaps because of preserved tubular function. These results are limited by the young cohort (mean age 13.8 months) and short follow-up period.Studies assessing hydroxyurea's effect on eGFR have showed conflicting results.48 children who started hydroxyurea before age 10 years were less likely to develop albuminuria, compared with those who started hydroxyurea after 10 years ; children on hydroxyurea in whom baseline albuminuria resolved received a higher dose of hydroxyurea . Larger controlled studies including adult patients are needed.The timing and dose of hydroxyurea initiation may affect albuminuria outcomes. In a retrospective analysis of data from 88 children with SCA,55 Older studies have demonstrated improved urinary concentration ability with simple transfusions; however, the capacity for recovery might be reduced with age.57 A retrospective review of 120 children and young adults with SCD found that patients who started chronic transfusion therapy at a younger age had a lower prevalence of microalbuminuria.52 They concluded that chronic transfusions were renoprotective when started younger than 9 years, while acknowledging significant transfusion-related adverse effects limiting routine use. However, another retrospective study evaluating risk of CKD progression in children did not note significant differences in the prevalence of microalbuminuria among treatment groups of hydroxyurea, chronic transfusions, or observation.51Chronic RBC transfusions (simple and exchange) can increase hemoglobin levels and decrease the amount of sickle RBCs in circulation, which has been shown to reduce markers of endothelial injury.l-glutamine was approved by the FDA in 2017, with the indication of reducing frequency of VOEs.58l-glutamine is an essential amino acid, and its mechanism of action in SCD is unknown. l-glutamine is essential for the synthesis of antioxidants NAD and GSH. As part of the oxidative stress that leads to hemolysis of HbS-containing RBCs, there is increased production of reactive oxidant species and free radicals that consume reduced NAD (reduced nicotinamide adenine dinucleotide) and GSH.5961 The depletion of reduced nicotinamide adenine dinucleotide and GSH is mitigated by glutamine, which is believed to decrease RBC damage and the threshold for hemolysis. Although one study found significantly decreased markers of hemolysis (reticulocytes and lactate dehydrogenase) in 19 patients on l-glutamine,62 the phase III approval study did not reproduce this finding.58 Previous studies support the role of glutamine in improving NAD redox potential and decreasing endothelial adhesion.61 Observational studies have focused on l-glutamine's effect on pain63 and other complications, and its effect on progression of renal disease in SCD is unknown.64 These include the suppression of inflammatory pathways and modulation of intestinal microbiome and barrier function to create a less aggressive SCD phenotype60 and glutamine acting to reduce resting energy expenditure.65 As with all supplements, caution should be used in patients with underlying liver disease or renal disease. Post hoc analysis of a randomized clinical trial assessing the use of l-glutamine in critically ill patients identified the greatest potential for harm in those with evidence for renal dysfunction at enrollment into the study.66Other reviews have discussed alternative mechanisms by which glutamine could affect erythrocytes.67 Crizanlizumab inhibits P-selectin binding to its ligands, presumably blocking P-selectin–mediated adhesion of inflammatory cells to the endothelium, thus reducing vaso-occlusion. Given its recent approval, there are ongoing evaluations68 into its clinical benefits, including its effect on nephropathy. The Study Exploring the Effect of Crizanlizumab on Kidney Function in Patients With Chronic Kidney Disease Caused by Sickle Cell Disease trial (NCT04053764) is a phase II study comparing crizanlizumab and standard of care with standard of care alone in patients with SCD-associated CKD. It is based on previous studies showing increased P-selectin expression in kidney ischemia-reperfusion injury.69 Its primary end point is the proportion of patients who experience ≥30% decrease in albuminuria at 12 months. In addition, the Study of Two Doses of Crizanlizumab Versus Placebo in Adolescent and Adult Sickle Cell Disease Patients trial (NCT03814746) is a phase III placebo-controlled trial comparing efficacy and safety of crizanlizumab doses with a secondary outcome of albuminuria prevalence.The monoclonal antibody crizanlizumab was approved by the FDA in 2019, with the indication of reducing VOE frequency.70 Voxelotor selectively and reversibly binds to hemoglobin, keeping it longer in the oxy-Hb or R-state. This results in delayed and decreased HbS polymerization, with less hemolysis and a modest increase in Hb concentration. The results from the long-term follow-up of the initial Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization study71 confirmed a durable increase in hemoglobin and noted significant improvement in markers of hemolysis  in the group randomized to 1500 mg of voxelotor. Given the noted effect on hemolysis markers,73 a small retrospective study evaluated albuminuria before and after voxelotor initiation in ten adult patients with SCA.74 They reported a 25% reduction in albuminuria from baseline in all patients placed on therapy, with a median decrease by 109 (−38 to −379) mg/g, compared with age-matched and sex-matched untreated controls that showed a 34% increase in albuminuria.Voxelotor was approved by the FDA in 2019, with the indication of increasing hemoglobin concentration.70 noted that the change in erythropoietin levels were similar across the groups, with a trend toward a lower erythropoietin level in the 1500 mg voxelotor group through week 24. This finding suggests that higher voxelotor hemoglobin occupancy, and higher hemoglobin, blunts the hypoxia-mediated induction of erythropoietin. An open-label study75 assessing voxelotor in participants with hepatic and renal impairment suggests no effect of kidney function on its excretion  but recommended dose reduction in severe hepatic impairment.The initial voxelotor trialNCT04335721). In addition, a next generation Hb-modifying agent, GBT021601, is being studied in a phase II/III clinical trial (NCT05431088) in adults and children.Like crizanlizumab, there are several ongoing trials further evaluating safety and efficacy including a randomized trial comparing risk of CKD progression in patients receiving voxelotor compared with standard of care  and percentage  change in albuminuria with treatment.Angiotensin inhibition with ACEi and angiotensin receptor blockers, cumulatively known as renin–angiotensin–aldosterone system (RAAS) blockers, used in other albuminuric/proteinuric kidney diseases and CKD,N=12) were placed on losartan for 1 year with renal function assessments at short (1–2 months) and long (≥12 months) time points.80 The albumin excretion rate decreased significantly in short-term but not at ≥12 months, although only eight patients completed long-term therapy. eGFR did not change significantly; thus, the use of losartan was believed to decrease albumin excretion with stable GFR. Another phase II multicenter trial with 6 months of losartan in adults and children with SCA met their primary end point of ≥25% reduction in albuminuria in the group of patients with microalbuminuria and macroalbuminuria.81More recently, angiotensin receptor blockers have been evaluated in a phase I study in which patients with SCA and persistent albuminuria . There was a statistically significant difference in the rate of eGFR decline between the groups with slower rate in the group on therapy.A large single-center retrospective review followed 86 patients on RAAS blockers for a median of 2.28 years compared with 68 patients not on therapy followed for 2.24 years.More long-term assessments of the efficacy and tolerance of RAAS blockade in this setting are needed, as well as prospective testing for synergism with SCD-related therapies.84 and canagliflozin has shown similar efficacy in albuminuric nephropathies.85Sodium–glucose cotransporter-2 inhibitors, used as antiglycemic agents now, have indication for use in CKD and albuminuric kidney diseases. Dapagliflozin and empagliflozin have demonstrated efficacy in slowing down CKD progression, independent of diabetes diagnosis,86 The placebo-controlled randomized study of participants with CKD receiving maximum tolerated doses of RAAS blockers showed significantly decreased risk of CKD progression in the finerenone group compared with placebo group but also higher rates of hyperkalemia. Because of its proposed ability to abrogate inflammation and fibrosis, both relevant in SCD nephropathy, some have suggested finerenone may have particular benefit for this disease entity.87Finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, was approved for diabetic kidney disease based on the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease study.The use of these therapies in SCD nephropathy has not yet been investigated; therefore, the benefits in this setting are unclear.A and ETB, of which ETA has proinflammatory, vasoconstrictive, and nociceptive actions. In SCD-associated oxidative stress, hypoxia, and vascular injury, the cellular synthesis of ET-1 is increased.88 ET-1 signaling contributes to development of chronic pain, vasculopathy, pulmonary hypertension, and CKD in SCD.88 Investigation of ET-1's role in nephropathy has shown high urinary ET-1 levels in patients with SCD and positive correlation between urinary albumin-creatinine ratio and serum ET-1 levels.89 In mouse models, ambrisentan, a selective ETA antagonist, has demonstrated efficacy in preventing nephropathy from the level of the glomerulus to the tubules.90 It is now being evaluated in a phase I trial (NCT02712346) with a secondary outcome measure of urinary microalbuminuria/proteinuria. Atrasentan, another selective ETA antagonist, which has been studied in diabetic nephropathy and CKD,91 is being evaluated (NCT04573920) for efficacy and safety in proteinuric glomerular diseases. Sparsentan, a dual angiotensin receptor and ETA antagonist, has been shown to decrease proteinuria in FSGS92 and is undergoing additional evaluation of its long-term efficacy in FSGS (NCT03493685) and in IgA nephropathy (NCT03762850). On the basis of prespecified interim analysis of the latter study which demonstrated greater reduction in proteinuria at 36 weeks when compared with irbesartan, sparsentan recently received accelerated approval for IgA nephropathy.93Endothelin (ET)-1 is a peptide that functions through binding to its receptors, ET95 which promotes deoxy-HbS polymerization and RBC sickling. PK activators increase ATP and reduce 2,3-DPG, thus reducing HbS polymerization, supporting RBC health and membrane integrity.Pyruvate kinase (PK) catalyzes the last step in glycolysis, resulting in generation of ATP. PK has a role in energy homeostasis, membrane integrity, and maintenance of 2,3-diphosphoglycerate , an intermediate of glycolysis. Elevated 2,3-DPG levels decrease oxygen affinity and pH in erythrocytes,96 They saw improvements in anti-HbS polymerization, noted by a reduction in the point of sickling (a novel biomarker demonstrating when sickling is initiated in vitro), an increase in measured Hb-oxygen affinity, ATP/2,3-DPG ratios, and total hemoglobin, with decreases in 2,3-DPG levels and hemolysis markers. The investigators are continuing the study over an extension period as a phase II/III study (NCT05031780). Etavopivat (FT-4202) is another PK activator that is being evaluated in SCD through the Study of Etavopivat in Adults and Adolescents With Sickle Cell Disease (NCT04624659).Mitapivat (AG-348) has demonstrated the ability to stabilize PK in sickle erythrocytes. A current phase II open-label study assessing efficacy and safety, reported on nine participants followed over 8 weeks.While these studies are not focused on nephropathy, data for GFR and albuminuria will be captured for both agents. The upstream targeting of HbS polymerization, as for voxelotor, might be predicted to result in improvements in hemolysis and anemia, with subsequent mitigation of kidney damage.98; therefore, deferasirox should be used cautiously and with frequent monitoring of renal function.Iron overload is an expected complication of chronic or recurrent transfusion therapy, indicated in many SCD-specific settings. Thus, iron chelation becomes necessary to prevent morbidity. Available chelating agents are deferoxamine, deferasirox, and deferiprone, and the choice of initiation depends on multiple factors. Deferasirox, a widely used oral chelator, has been implicated in kidney-specific adverse events ranging from dose-dependent but reversible elevations in creatinine to renal failure99 and contribute to renal insufficiency. In addition, recurrent use of NSAIDs carries the risk for acute kidney injury, which itself is a factor for developing CKD.100Nonsteroidal anti-inflammatory drugs (NSAIDs) play a role in SCD-mediated pain management but should be used sparingly in the setting of sickle nephropathy. In the presence of nephropathy, the vasoconstrictive mechanism of NSAIDs can worsen glomerular hyperfiltrationNephropathy, up to and including ESKD, in SCD is an important predictor of mortality. The pathophysiology of SCD-associated nephropathy is multifactorial; however, the proximate cause is hemoglobin polymerization and its downstream consequences.Newer SCD-directed therapies target aspects of the disease implicated in renal damage, including rate of RBC polymerization, anemia, hemolysis, endothelial adhesion, and vascular inflammation Figure . The useThe literature contains mostly small, observational studies, so there is need for larger, longer-term, prospective, controlled, and real-world studies to better evaluate the effect of interventions on albuminuria, eGFR, tubular dysfunction, and overall renal health. Future directions for research include elucidating mechanisms of action of these therapeutics, clarifying the role of biomarkers in diagnosing renal damage and its response to therapy, and testing for potential synergism between therapeutic strategies.V.K. Derebail reports the following—consultancy: Bayer, Forma Therapeutics, Merck, Novartis, and Travere; honoraria: UpToDate; and research funding: Site PI for Clinical Trials . J. Little reports the following—advisory or leadership role: Husband Tom Hostetter advisor for Tricida is not being paid for this currently or in recent past; patents or royalties: On patents currently being used at BioChip Labs and Hemex, but I receive no royalties or financial rewards from this; research funding: BlueBird Bio and GBT (Pfizer); and other interests or relationships: Member of National Association of Sickle Cell Centers and receive funding; receive funding from NHLBI; on study adjudication for Forma/Norva Nordisk Ph III Hibiscus Study. All remaining authors have nothing to disclose.


The effects of increased positive end-expiratory pressure (PEEP) on PbtO2 and intracranial pressure (ICP) needs to be further elucidated. This is a single center retrospective cohort study (2016–2021) conducted in a 34-bed Department of Intensive Care unit. All patients with acute brain injury under mechanical ventilation who were monitored with intracranial pressure and brain tissue oxygenation (PbtO2) catheters and underwent at least one PEEP increment were included in the study. Primary outcome was the rate of PbtO2 responders (increase in PbtO2 > 20% of baseline) after PEEP increase. ΔPEEP was defined as the difference between PEEP at 1 h and PEEP at baseline; similarly ΔPbtO2 was defined as the difference between PbtO2 at 1 h after PEEP incrementation and PbtO2 at baseline. We included 112 patients who underwent 295 episodes of PEEP increase. Overall, the median PEEP increased form 6 (IQR 5–8) to 10 (IQR 8–12) cmH2O (p = 0.001), the median PbtO2 increased from 21 (IQR 16–29) mmHg to 23 (IQR 18–30) mmHg (p = 0.001), while ICP remained unchanged . Of 163 episode of PEEP increments with concomitant PbtO2 monitoring, 34 (21%) were PbtO2 responders. A lower baseline PbtO2 (OR 0.83 [0.73–0.96)]) was associated with the probability of being responder. ICP increased in 142/295 episodes of PEEP increments (58%); no baseline variable was able to identify this response. In PbtO2 responders there was a moderate positive correlation between ΔPbtO2 and ΔPEEP (r = 0.459 [95% CI 0.133–0.696]. The response in PbtO2 and ICP to PEEP elevations in brain injury patients is highly variable. Lower PbtO2 values at baseline could predict a significant increase in brain oxygenation after PEEP increase.Cerebral hypoxia is an important cause of secondary brain injury. Improving systemic oxygenation may increase brain tissue oxygenation (PbtO Cerebral hypoxia is an important cause of secondary brain injury and can frequently affect ABI patients with both traumatic and non-traumatic etiology6. Indeed, low brain tissue partial pressure of oxygen (PbtO2) has been associated with cerebral anaerobic metabolism, increased risk of mortality and poor functional outcome13.Prevention, identification and early treatment of secondary brain injury is an important aspect of the management of acute brain injury (ABI) in order to improve outcome2 is a focal measurement of brain oxygenation reflecting an equilibrium between oxygen delivery , consumption  and extraction 15. Therefore, different pathophysiological mechanisms are associated with low PbtO2 after acute brain injury, such as reduced CBF and/or cerebral perfusion pressure (CPP), intracranial hypertension (IH), hypoxemia, anemia, altered microcirculation or excessive cellular metabolism16. Hypoxemia itself has also been associated with poor outcomes after traumatic brain injury18. Therefore, strategies aiming at improving hypoxemia may be useful in this setting.PbtO22. These effects are more pronounced in patients with acute respiratory distress syndrome (ARDS)24. By improving systemic oxygenation, increased PEEP could improve brain tissue oxygenation. However, the existing literature is scarce. Small studies have shown an increase in PbtO2 following increases in PEEP and recruitment manouvers26, while others have not27. Moreover, while PEEP may increase PbtO2 by increasing systemic oxygenation, it can potentially also increase ICP, by reducing cerebral venous outflow due to increased intrathoracic pressure28, or decrease mean arterial pressure (MAP), by impairing venous return to the heart29.In patient undergoing mechanical ventilation, applying a positive end-expiratory pressure (PEEP) has been shown to reduce end-expiratory alveolar collapse, maintaining alveolar recruitment and possibly reduce the incidence of ventilator-associated pneumonia and lung injury2 and ICP in ABI patients. The secondary aim was to identify baseline factors associated with PbtO2 increase and ICP increase.Therefore, the aim of this study was to assess the impact of increase in PEEP levels on PbtO30.This was a single center retrospective cohort study conducted at the Intensive Care Unit (ICU) of the Hôpital Universitaire de Bruxelles (HUB), in Brussels, Belgium, from January 2016 to December 2021. The study protocol was approved by Erasme Hospital Ethics Committee (P2022/449) and the need for informed written consent was waived, because of the anonymized data collection of retrospective data. This study was carried out in accordance with the Strengthening The Reporting of Observational studies in Epidemiology (STROBE) statement2 monitoring within the first 48 h of admission and (c) patients underwent at least one increase in PEEP levels concomitantly with the use of neuromonitoring. Patients with imminent death were excluded.We screened adult (> 18 years) patients admitted to the ICU due to an acute brain injury. Inclusion criteria were: (a) traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (aSAH) patients under controlled mechanical ventilation; (b) the presence of ICP and PbtO31 and SAH32; invasive multimodal monitoring, including PbtO2, was implemented according to recent consensus1. PbtO2 monitoring is considered as “standard of care” for ABI patients with a Glasgow Coma Score (GCS) < 9 and requiring intracranial pressure (ICP) monitoring; PbtO2 probes were placed in the frontal region of the hemisphere at greatest risk for secondary brain injury. In TBI patients, probe was placed close < 5 cm to the most injured/contused area in TBI; in SAH patients probes were placed in the region at risk or with demonstrated delayed cerebral ischemia for aSAH). Probes were inserted through a frontal burr hole using a triple-lumen bolt. PbtO2 was monitored continuously using a specific probe and the Integra Licox® Brain Tissue Oxygen Monitoring System . Probe location was confirmed by a cerebral CT-scan performed within 24 h from neuromonitoring placement. The adequate functioning of the probe was tested with a 100% oxygen fraction (FiO2) test for 15 min (i.e. an increase of at least 5 mmHg of PbtO2 indicated an adequate catheter function). Intracranial pressure probes were placed either intraventricular or intraparenchymal.We followed the current guidelines for the management of TBI33 by implementing a lung protective ventilation strategy and targeting Plateau pressure < 30 mmHg and driving pressure < 15 mmHg34. If after one 1 h of PEEP incrementation there was no benefit in oxygenation or if there were deleterious effects on respiratory mechanics or persistent hemodynamic instability, PEEP was reversed to baseline setting. The decision on the amount of PEEP to incrementation was done by the respiratory therapist in agreement with the treatment treating physician. No FiO2 changes were implemented during the PEEP trial.PEEP was increased according to the decision of the critical care team responsible for the treatment of the patient. There was no standardized protocol. However, PEEP was increased in increments of 2 mmHg for at least 1 h-aiming at improving systemic oxygenation  and respiratory mechanics while minimizing ventilator induced lung injury2 were measured in real-time and collected prospectively on a patient data monitoring system. Cerebral perfusion pressure (CPP) was calculated as the difference between MAP and ICP; MAP was zeroed at the level of the left atrium. Intracranial hypertension was defined as ICP value above 20 mmHg for at least 5 min at any time. Brain tissue hypoxia was defined as a PbtO2 < 20 mmHg for at least 5 min.Physiological variables, ICP and PbtO2. ICP and PbtO2 were recorded prospectively every minute. Data was extracted from the monitoring system and the mean value of ICP and PbtO2 was calculated for every hour of monitoring.Baseline (T0) was defined as the hour immediately preceding a PEEP change and T1 was defined as the first 1 h with the new stable PEEP value. The 60-min mean of value of the following continuous variables was collected at T0 and T1: mean arterial pressure (MAP), heart rate (HR), ICP, CPP and PbtO2 changes (ΔICP and ΔPbtO2) were calculated as the difference between ICP or PbtO2 at T1 and T0. A “decrease” in ICP or PbtO2 was identified as a ΔICP/ΔPbtO2 < 0; a “stable” value as a ΔICP/ΔPbtO2 = 0 and an “increase” as a ΔICP/ΔPbtO2 > 0. Patients with a PbtO2 increase of more than 20% from baseline were considered as “responders”; a significant increase in ICP was defined as an increase of more than 20% from baseline or an increase that led to intracranial hypertension. The following ventilator parameters were recorded at T0 and T1: inspiratory pressure (Pins); tidal volume (VT), PEEP; respiratory rate (RR) and inspired fraction of oxygen (FiO2). Arterial oxygen saturation (SaO2), lactate, pH, PaCO2, PaO2 were also recorded.ICP and PbtO35 and the Glasgow coma scale (GCS)36 on admission. Hospital mortality and the Glasgow Outcome Scale (GOS)37 at 3 months were collected, as previously reported38. Unfavorable neurological outcome (UO) was defined as GOS of 1–3.We collected demographics, the presence of comorbidities, sequential organ failure assessment (SOFA)2 responders. Secondary outcomes included: (a) the proportion of patients with an increase of ICP > 20% or an increase in ICP that resulted in intracranial hypertension after PEEP augmentation; (b) the correlation between the difference of PEEP at T1 and T0 (ΔPEEP) and ΔICP/ΔPbtO2; (c) baseline factors associated with significant increases in PbtO2 and ICP after PEEP augmentation; (d) the proportion of patients with an decrease in CPP resulting on a CPP < 60 mmHg; (e) differences between the trends in PbtO2 and ICP during PEP incrementation challenge in SAH and TBI patients.The primary outcome was the proportion of PbtO, ΔPbtO2, ΔICP, ΔCPP and ΔPaO2. As a sensitivity analysis we also considered just the first PEEP increment of each patient to calculate the correlation between ΔPEEP, ΔPbtO2, ΔICP, ΔCPP and ΔPaO2. To account for multiple measures per patient a generalized mixed model with logit link was used to identify baseline variables which were independently associated with a PbtO2 responder and a significant increase in ICP after PEEP increment; baseline variables with a p value < 0.1 in the univariate analysis were included in the multivariable analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were computed for all variables. The independence of errors, presence of multicollinearity and of influential outlier assumptions were checked; none were violated. A receiver operator curve was designed to assess the sensitivity and specificity of baseline PbtO2 to identify responders. The area under the curve (AUROC) and CI 95% were computed. Youden’s test was used to identify the cut-off with the best sensitivity and specificity. We used a similar model to identify variables associated with an absolute increase in PbtO2 and ICP after PEEP increments. All statistical analyses were performed using SPSS 27.0 for MacIntosh. A p value < 0.05 was considered significant.Descriptive statistics were computed for all variables. Categorical variables were described as proportions (%) and compared using Chi square or Fisher’s exact test. Normality was assessed using the Kolmogorov–Smirnov test. Normally distributed variables were expressed as mean (± SD) and compared using Student t test while non-gaussian continuous variables were described median [IQRs] and compared using Mann–Whitney test (independent variables) or Wilcoxon test (repeated measures of related variables). A Spearman correlation was computed between ΔPEEPThe study protocol was approved by local ethics Committees  and informed written consent was waived. All methods were carried out in accordance with relevant scientific and ethical guidelines and regulations.2 during the study period, 112 patients  had an increase in PEEP values under controlled mechanical ventilation . The characteristics of the population are shown in Table 2O (p = 0.001); PbtO2 significantly increased from 21 (16–29) to 23 (18–30) mmHg (p = 0.001), while ICP remained stable over time, varying from 12 (7–18) to 12 (7–17) mmHg (p = 0.42), as shown in Fig. Over a total of 237 patients monitored with ICP and PbtO2 in 102/163 (63%) episodes of PEEP augmentation; in 30 (18%) episodes, there were no changes in PbtO2, while in 31 (19%) episodes there was a decrease in PbtO2. Baseline PbtO2 was below 20 mmHg in 63/163 (39%) episodes. Higher baseline PaO2 (OR 1.02 [95% CI 1.01–1.03]) and lower baseline PbtO2 (OR 0.92 [95% CI 0.91–0.94]) were independently associated with any increase in PbtO2 after PEEP augmentation ; considering only the first measure per patient, a weak correlation between ΔPbtO2 and ΔPaO2 was observed (r = 0.275 [95% CI 0.0254 to 0.530]).There was no correlation between ΔPEEP and ΔPbtO2 responders after PEEP incrementation; lower levels of baseline PbtO2 were associated with being a responder (Table 2 cut-off with the best sensitivity (91.2%) and specificity (66.7%) was 21 mmHg.We identified 34/163 21%) PbtO1% PbtO2 2 responders, there was a moderate positive correlation between ΔPbtO2 and ΔPEEP (r = 0.459 [95% CI 0.133 to 0.696]), ΔPbtO2 and ΔPaO2 (r = 0.382 [95% CI 0.001 to 0.672]), while no correlation between ΔPbtO2 and ΔCPP was found (r = − 0.027 [95% CI − 0.371 to 0.324]), as shown in Fig. 2 and ΔCPP (r = 0.196 [95% CI 0.019 to 0.361]), ΔPbtO2 and ΔPaO2 (r = 0.213 [95% CI 0.012 to 0.418]), while no correlation between ΔPbtO2 and ΔPEEP was observed  episodes of PEEP augmentation, there was an absolute increase in ICP. Baseline ICP was above 20 mmHg in 49/295 episodes (17%). No baseline factors were associated with an absolute ICP increase after PEEP augmentation  episodes of PEEP incrementation. In 23/109 (21%) episodes of significant ICP increase there was an ICP increase > 20% resulting in an ICP > 20 mmHg at T1. No baseline factors were associated with a significant ICP increase Table . In patiOf note, in only 4/295 (1.4%) episodes of PEEP incrementation resulted in a CPP of < 60 mmHg.A significant CPP reduction (T1 CPP < 60 mmhg) was observed in /295.2O (p = 0.001); PbtO2 significantly increased from 20 (15–25) to 22 (18–28) mmHg (p = 0.001), while ICP did not vary significantly over [from 13 (7–18) to 12 (7–16) mmHg (p = 0.56)]. CPP also remained stable over time [ from 86 (78–95) to 85 (74–95) mmHg (p = 0.50]. There was an absolute increase in PbtO2 in 42/59 (71%) episodes of PEEP augmentation; however, only in 13 (22%) episodes there was a significant increase in PbtO2 (PbtO2 responders). In 11 (17%) episodes, there were no changes in PbtO2 while in 6 (10%) episodes there was a decrease in PbtO2. In 52/122 (43%) episodes of PEEP augmentation in TBI patients, there was an absolute increase in ICP, while a significant increase in ICP was observed in 38/122 (31%) episodes.In TBI patients (n = 48) PEEP was increased from 5 (5–8) to 10 (8–12) cmH2O (p = 0.001); PbtO2 significantly increased from 23 (16–32) to 24 (18–32) mmHg (p = 0.001), while ICP did not vary significantly over [from 12 (7–18) to 12 (7–18) mmHg (p = 0.24)]. CPP also remained stable over time [from 96 (82–110) to 96 (79–110) mmHg (p = 0.73]. There was an absolute increase in PbtO2 in 60/104 (58%) episodes of PEEP augmentation; however, we identified only in 21/104 (20%) PbtO2 responders. In 19/104 (18%) episodes, there were no changes in PbtO2 while in 25/104 (24%) episodes there was a decrease in PbtO2. In 52/173 (31%) episodes of PEEP augmentation in SAH patients, there was an absolute increase in ICP, while a significant increase in ICP was observed in 54/122 (26%) episodes.In SAH patients (n = 65) PEEP was increased from 6 (5–8) to 10 (8–12) cmH2 and ICP variation of time after PEEP challenges as shown in Supplemental Fig. S3.Patient with TBI and SAH had similar trends regarding PbtO2 in 35% of episodes following an increase in PEEP; a lower baseline PbtO2 was found to be associated with a significant increase in brain oxygenation. We determined that a baseline PbtO2 cut-off of 21 mmHg was optimal for identifying PbtO2 responders to PEEP. Additionally, we observed a moderate correlation between changes in PEEP and changes in PbtO2, specifically within the group of PbtO2 responders. Interestingly, we did not identify any baseline factors associated with a significant increase in ICP, which was observed in 37% cases following PEEP augmentation.In this study, we observed a significant elevation in PbtO37. The use of PEEP is a crucial component of ventilation strategies in this context. Recent consensus guidelines38 suggest that in acute brain injury patients without acute respiratory failure, PEEP levels should be similar to those used in patients without brain injury, and lung protective ventilation strategies can be employed. In patients with both respiratory failure and acute brain injury, lung protective ventilation and higher levels of PEEP may be utilized, as long as clinically significant increases in ICP are not observed. However, there are currently no specific recommendations provided for patients with acute brain injury, respiratory failure and intracranial hypertension38.Mechanical ventilation is often required for patients with severe TBI and poor-grade SAH due to various factors, such as coma, compromised airway protection, risk of aspiration, seizures, elevated ICP, pulmonary dysfunction, and respiratory failure resulting from pre-existing conditions or new complications2 range of 80–120 mmHg to avoid both hypoxemia and hyperoxia38. Positive end-expiratory pressure plays a crucial role in increasing lung functional residual capacity, preventing alveolar de-recruitment, and improving oxygenation37. Therefore, increasing PEEP can be a strategy to enhance oxygenation in these patients. Another important consideration in setting PEEP is PbtO2, as avoiding cerebral hypoxia, in addition to systemic hypoxemia, is crucial in preventing secondary brain injury in neurocritical care. Additionally, acute lung injury has been associated with brain tissue hypoxia39. However, there is limited research on the impact of PEEP on brain oxygenation.These consensus guidelines have also recommended targeting a PaO2O resulted in significant increases in PbtO2 and oxygen saturation, without affecting ICP or CPP in patients without baseline intracranial hypertension25. Another study with 10 SAH patients showed that applying PEEP of 20 cmH2O resulted in a decrease in PbtO2 due to a simultaneous decrease in CPP and cerebral blood flow, which was reversed upon restoration of MAP27. Furthermore, a study involving a mixed population of SAH and TBI patients with ARDS demonstrated that recruitment maneuvers and high levels of PEEP significantly improved both systemic and brain tissue oxygenation, leading to reduced oxygen requirements26. In our study, increasing PEEP improved PbtO2, particularly in patients with low baseline PbtO2. Similar responses have been observed with other strategies aimed at enhancing interstitial oxygen availability in acute brain injury patients, such as red blood cell transfusion40.One study involving 20 TBI patients with ARDS demonstrated that increasing PEEP from 5 to 10 to 15 cmH41. Hypotension is a significant cause of secondary brain injury, as it can reduce CPP and induce ischemia43. Previous studies that reported negative effects of PEEP on CPP are typically associated with decreased mean arterial pressure46. In our study, both MAP and CPP remained unchanged. It is important to note that increased intrathoracic pressure can lead to decreased cerebral venous drainage, which may elevate ICP28. Additionally, higher levels of PEEP and low tidal volumes can result in increased arterial carbon dioxide levels, potentially causing cerebral vasodilation and a subsequent increase in ICP47. Consequently, numerous studies have investigated the effects of PEEP on ICP and cerebral hemodynamics.The application of PEEP can have an impact on cardiovascular physiology by increasing intrathoracic pressure; this can potentially decrease venous return, reduce cardiac output, and lead to hypotension, particularly in hypovolemic patients48. Boone et al. showed minimal effects of PEEP on ICP in patients without severe lung injury, and even in severe lung injury patients, the increase in ICP due to PEEP was considered clinically irrelevant44. Other studies conducted in patients with ischemic stroke and TBI have also indicated that the response of ICP to PEEP, although variable, is moderate at best and lacks clinical impact, suggesting that PEEP can be safely utilized in acute brain injury patients when indicated52. These findings are consistent with our study. However, an older study reported a significant increase in ICP after increments in PEEP among head-injured patients, which had neurological repercussions and necessitated immediate reduction in PEEP28.Wolf et al. demonstrated that employing an open lung strategy with PEEP appears to be safe in patients with acute brain injury and concomitant ARDS, as evidenced by no significant changes in ICP in a small case series (n = 11)2O resulted in increases in ICP without clinical relevance, as CPP remained stable and above 60 mmHg50. Other studies have shown that in patients with ICP > 20 mmHg, ICP decreased or remained stable after PEEP increments, while CPP remained unchanged or even increased in some cases52. In our study, significant increases in ICP due to PEEP increments were observed in 37% (109/295) of episodes, with an ICP exceeding 20 mmHg in 34% (37/109) of episodes. However, baseline ICP was not found to be an independent factor associated with ICP increases following PEEP increments. We were unable to identify any baseline factors that could predict changes in ICP in response to PEEP. Similarly, a recent study also failed to identify baseline factors that could help identify patients at higher risk for ICP increases following PEEP changes46.The impact of PEEP on ICP appears to be influenced by the presence of baseline intracranial hypertension. One study that analyzed changes in ICP after incremental increases in PEEP found that in patients with baseline intracranial hypertension, higher PEEP levels did not affect ICP, while in patients with normal ICP, PEEP levels of 10 and 15 cmH53. Conversely, in patients with normal compliance, there was a decrease in CPP and cerebral blood flow, but no changes in ICP45. A recent study has demonstrated that changes in ICP are inversely correlated with lung recruitability after PEEP application and recruitment maneuvers, suggesting that patients who would benefit from higher PEEP levels will have minimal side effects on intracranial pressure46. This can be explained by the fact that the detrimental effects of PEEP are related to alveolar hyperinflation, leading to a significant increase in arterial carbon dioxide and intrathoracic pressure. Conversely, when PEEP leads to alveolar recruitment, improved lung gas distribution, and optimization of ventilation/perfusion matching, ICP remains unchanged46. In our study, PaCO2 remained stable and within the normal range, which may explain why overall ICP remained unchanged.Another factor that appears to influence ICP responses to variations in PEEP is lung compliance. In patients with low compliance, as is often the case in ARDS patients, higher levels of PEEP had no impact on CPP, ICP or cerebral blood flow2 after PEEP increments and functional outcomes. Moreover, the retrospective design of our study prevents us from ruling out the potential influence of other concurrent interventions, sedation, or vasopressor therapy, which may have contributed to the observed changes in PbtO2 following PEEP increments. Additionally, we lack information on the specific reasons for PEEP changes, as these were determined by the clinical care team. Importantly, we were unable to assess change in respiratory mechanics (such as lung compliance) and correlate them to PbtO2 and ICP due to the retrospective nature of this study. Furthermore, the magnitude of PEEP changes in our study was generally small, which could have impacted our results. Moreover, due to how the data was collected (1 h mean) we were unable to perform a time series analysis of the impact of PEEP incrementation on physiological variables. It is also important to note that while PbtO2 may assess interstitial oxygen availability, its influence on cellular oxygenation in the brain remains uncertain. Lastly, our findings are not conclusive, as the heterogeneity of our study cohort, which included both traumatic and non-traumatic brain injury patients, and the placement of the probe in hypo perfused cerebral areas (which are more sensitive to interventions aiming to improve oxygen delivery), as well as the use of regional rather than global oxygen monitoring, raise significant issues that should be addressed in future studies on this topic.Our study has several limitations that should be acknowledged. Firstly, we did not perform a formal sample size calculation, which may have limited the power of our study and prevented us from drawing definitive conclusions. Additionally, this was a single-center study, and therefore, the generalizability of our findings to other centers may be limited. Due to the limited number of events, we were unable to conduct further subgroup analyses, such as comparing patients with baseline tissue hypoxia, baseline intracranial hypertension or differentiating those with ARDS from those without ARDS, which could provide valuable insights into specific patient populations. Another limitation is that we did not specifically assess the correlation between increases in PbtO2 could be a viable approach in patients with acute brain injury, particularly those presenting with baseline tissue hypoxia. However, it is crucial to closely monitor ICP and systemic hemodynamics to ensure the safe and appropriate administration of PEEP.In this study, implementing PEEP to enhance PbtOSupplementary Information.


A Kaplan–Meier analysis showed that the probability of freedom from events was significant in patients who exhibited a combination of higher NT-proBNP and Galectin-3 levels (log-rank p = 0.032). Therefore, NT-proBNP was the most reliable predictor of events in asymptomatic patients with severe AS. A combination of NT-proBNP and Galectin-3 levels may be vital in the clinical follow-up of these patients and in the decision-making process.Recognizing symptoms in elderly patients with severe aortic stenosis (AS) can be a challenge. Serum biomarkers such as Galectin-3 or N-terminal prohormone B-type natriuretic peptide (NT-proBNP) are involved in remodeling and heart failure (HF) development and could support the diagnosis of AS. We set out to test the usefulness of NT-proBNP and Galectin-3 in predicting events in this population. We designed a prospective observational case–control study, including 50 asymptomatic patients older than 70 years, diagnosed with severe degenerative AS, and 50 control individuals. The NT-proBNP and Galectin-3 levels were measured. A follow-up was carried out at 12 months to determine the occurrence of hospital admission for HF, all-cause mortality or the appearance of symptoms. The patients with severe AS had higher Galectin-3 and NT-proBNP concentrations. The area under the receiver operating characteristic curve of the NT-proBNP was 0.812 , and that of the Galectin-3 was 0.633 . NT-proBNP was a good predictor of events [HR 3.45 (95% CI 1.32–9.03),  Aortic stenosis (AS) is the most frequent valve pathology in clinical practice . A degenCurrently, two invasive treatment options are available for patients with severe AS, aortic valve replacement surgery (AVR) and transcatheter aortic valve implantation (TAVI); the former is more appropriate for patients older than 75 years and those with intermediate and high surgical risk, as long as there is no risk of failure .Diagnosing AS in the elderly is challenging. First, recognizing symptoms in older patients can be difficult, due to the presence of comorbidities that negatively influence physical activity or because the patients unconsciously limit themselves physically in such a way that they do not report any symptoms. In addition, the collection of medical history data could be even more complicated if this aging population presents with cognitive impairment such as dementia or delirium ,6; thereGalectin-3 belongs to the β-galactoside-binding protein family and serves important functions in numerous biological activities, including cell growth, apoptosis, differentiation, inflammation and fibrosis . Recent The identification of high-risk populations is critical to avoid readmission and high-rate mortality and thus achieve effective management and use of resources. However, indications for invasive medical treatment among frail elderly patients with severe AS are limited because of the lack of symptoms, difficulties in performing diagnostic tests or the condition itself, which can cause delayed timing. In the current study, we aimed to test the usefulness of NT-proBNP and Galectin-3 in an older population with asymptomatic severe AS.This is a prospective, observational, case–control study. Two cohorts were recruited: (i) patients older than 70 years diagnosed with asymptomatic severe degenerative AS (n = 50) and (ii) healthy controls who were matched by age and sex. The patients were recruited from cardiology outpatient clinics. Patients with severe concomitant valvulopathies, patients under 70 years of age, and patients with severe AS who were symptomatic or pending intervention were excluded. The control group consisted of individuals who showed a normal clinical examination and did not present with any chronic heart condition except high blood pressure (HBP). The case recruitment was performed from August 2017 to July 2018, and the control cohort was included from December 2020 to May 2021.The study protocol was approved by the Ethics Committee of Alfonso X el Sabio University/UAX and met the ethical criteria of the Declaration of Helsinki. Signed informed consent was obtained from all patients.Biodemographic data were collected, including age, sex, weight, height, body mass index (BMI) and body surface area (BSA), using the DuBois and DuBois formula. The clinical variables analyzed included unhealthy habits and cardiovascular risk factors such as HBP, diabetes mellitus (DM) or dyslipidemia (DLP). The presence of atrial fibrillation (AF), ischemic heart disease, and comorbidities included in the Charlson index were also collected . A physi2 to also include severe AS with a low gradient [All the patients underwent comprehensive Doppler echocardiography on study recruitment with a Phillips Affinity-70C echocardiograph with an S5-1 probe by an experienced echocardiographer. The severity of aortic valve disease was calculated following the recommendations of the European Society of Cardiology by evaluating the maximum velocity (Vmax), the mean pressure gradient (MPG) and the aortic valve area (AVA), calculated using the continuity equation and the dimensionless index (DI) or integral relation, which represents the ratio of the left ventricular outflow tract (LVOT) time-velocity integral to that of the aortic valve jet . Severe gradient ,17.Two-dimensional measurements of the left ventricular (LV) diameter and wall thickness and the left atrial volume were also performed. The left ventricular ejection fraction (LVEF) was calculated using the four-chamber and two-chamber Simpson biplane methods and was considered preserved above 50% and reduced when it was ≤50% .The LV diastolic function and filling pressures were assessed according to the recommendations of the European Association of Cardiovascular Imaging . The gloThe size and function of the right ventricle and the estimation of systolic pulmonary arterial pressure (sPAP) were evaluated following the guidelines of the European Society of Cardiology .All the blood samples were taken from a peripheral vein and processed under identical conditions at 08:00 h after 12 h of fasting and within 48 h of echocardiography. The Galectin-3 samples and NT-proBNP were analyzed at the laboratory using a fluorescent enzyme-linked immunoassay on the VIDAS analyzer .The Galectin-3 level was classified into three groups according to the cutoff previously proposed for risk stratification in established HF. High risk was considered when it was >25.9 ng/mL, moderate risk > 17.8–25.9 ng/mL and low risk ≤ 17.8 ng/mL . We also2 [The estimated glomerular filtration rate (eGFR) was calculated by the Chronic Kidney Disease Epidemiology Collaboration equation. Renal function was considered impaired when the eGFR < 60 mL/min/1.73 m2 .The recruited patients were followed up at six months and one year in cardiology clinics or by telephone when the patient was unable to attend. For evaluating the results, the endpoint of the study was defined as the occurrence of death from any cause, admission for CHF or the appearance of symptoms  and a change in treatment . Likewise, the different causes of mortality were collected.www.stata.com accessed on 18 October 2022) was used for the statistical analysis. For the description of the data, the frequency and percentages are used for the qualitative variables, and the means (standard deviation), median  and minimum/maximum are used for the quantitative variables. Comparisons between the quantitative variables were made using the independent samples Student’s t-test for the variables with a normal distribution according to the Kolmogorov–Smirnov test. For the variables that did not conform to normality, the Mann–Whitney U test was used. The qualitative variables are shown as total numbers and percentages. The comparisons between the qualitative variables were made using Pearson’s χ2 test with Yates’s correction or Fisher’s exact test as appropriate.Stata 15.1 software  curve analysis. The area under the curve and the sensitivity and specificity values were calculated, all with 95% confidence intervals.A Kaplan–Meier analysis was performed to study the event-free survival curve (time-to-first-event), in this case, the combined endpoint by groups was based on their Galectin-3 levels, NT-proBNP levels and the combination of both, according to the cutoff points obtained from the ROC curve analysis. The differences between the two groups were evaluated with the log-rank test.p-value < 0.22) and created overfitting, as was the case for Vmax and the integral relation, which created significant distortions in the form of outliers.A univariate Cox proportional hazards regression analysis was performed to detect the independent predictors of major adverse cardiac events (MACEs). A multivariate model was made with all the significant variables in the univariate analysis. We then removed the variables that did not provide information to the model  mmHg and 33.36 (12.9) mmHg, respectively. As expected, the AS group showed significantly increased LV wall thickness, with a higher percentage of hypertrophy severity. The LVEF was slightly higher in the control group, but not significantly so. The sPAP was higher in the case group. Although the GLS was lower in the AS patients than in the control group, the difference was not significant. When a value of −18% was used as the cutoff point, there was a significant difference between both groups, with the group with AS presenting a higher GLS percentage below this limit (19 vs. 7 patients).The AVA index ranged between 0.23 and 0.65 cmAmong the 50 patients with AS, 3 (6%) died during the follow-up year, 4 (8%) were admitted for CHF, 2 (4%) underwent AVR surgery and 10 (20%) underwent TAVI after developing symptoms. The causes of death were not of cardiac origin in any of the three patients.We further tested the correlations between the Galectin-3 and NT-proBNP levels and significant parameters of AS severity (mean gradients and AVA), as well as the indices of LV remodeling, such as the thickness of the interventricular septum (IVS) and the GLS .There were moderate correlations between the echocardiographic parameters of AS severity and the tested biomarkers, with the NT-proBNP demonstrating greater correlations than the Galectin-3. Both the Galectin-3 and NT-proBNP levels were also positively correlated with IVS, but neither was correlated with the GLS. NT-proBNP but not Galectin-3 was significantly correlated with age.The univariate analysis by logistic regression yielded a statistically significant direct correlation between NT-proBNP and the occurrence of MACEs, while no such correlation was identified for Galectin-3. Most of the echocardiographic parameters associated with the severity of stenosis  were associated with MACEs, while no association was found between impaired GLS and MACEs. In the multivariable analysis, only the level of NT-proBNP remained statistically significant when treated as a continuous variable .The area under the receiver operating characteristic curves was 0.81 (95% CI: 0.7111–0.9135) for the NT-proBNP and 0.63 (95% CI: 0.5082–0.759) for the Galectin-3 . The senp = 0.15). The levels of Galectin-3, however, were not predictive of MACEs (p = 0.59). Notably, the combination of both biomarkers led to a statistically significant prediction of events (p = 0.032)  and Galectin-3 (14.3 ng/mL). A Kaplan–Meier analysis was used to assess the correlation over time between Galectin-3 ≥ 14.3 ng/mL, NT-proBNP > 435 pg/mL and the combination of both and overall MACE occurrence. Although the NT-proBNP produced a yield curve, no statistically significant difference was found between the groups (= 0.032) .The valvular disease AS is a newly emerging pandemic in elderly individuals due to the aging of the population in the Western world. Performing a correct diagnosis in the frail and aged population with AS is a vital problem that often leads to a timing delay in delivering interventional options. Our study assesses the prognostic reliability of the biomarkers NT-proBNP and Galectin-3 in asymptomatic elderly patients with severe AS, which has not been researched to date.In our study population, we found increased levels of both biomarkers in older patients with asymptomatic AS compared to the control group. Although only NT-proBNP was a good event discriminator in the multivariate analysis, the combination of both biomarkers depicted powerful stratification capabilities using a Galectin-3 level of 14.3 pg/mL and an NT-proBNP level of 435 pg/mL. The role of these two biological markers in increasing diagnostic accuracy has been previously revealed by studies such as that of Feola et al. , carried2 was required in our study to classify these patients with low gradient and low flow as having severe AS [The diagnosis of severe AS is challenging and requires careful exclusion of measurement errors and other explanations for the echocardiographic findings , as wellevere AS . ClinicaAmong the studies that systematically reviewed the role of Galectin-3 in AS biological processes, most of the studies reported all-cause mortality , but fewGalectin-3 has been shown to be related to chronic CHF and myocardial fibrosis in numerous publications, but studies in asymptomatic patients with severe AS are scarce; most of them have been carried out when following up operated patients or patient populations spanning several degrees of AS severity ,30,31. AGalectin-3 levels in the general population described in other studies vary from 10 to 13 ng/mL to 15–30 ng/mL in patients with CHF ,35,36. HArangalage et al.  independDespite these unsatisfactory results in predicting events, the known relationship between Galectin-3 and the presence of inflammation and fibrosis could have potential usefulness in leading asymptomatic AS patients with high Galectin-3 levels to undergo cardiac magnetic resonance imaging (MRI) using gadolinium to assess LV fibrosis before TAVI. The presence of myocardial fibrosis is associated with incomplete functional recovery and worse outcomes after TAVI . RoutineUnlike Galectin-3, NT-proBNP performed well, yielding more reasonable sensitivity and specificity in predicting the occurrence of MACEs, which is consistent with previous studies ,38,39. ITherefore, to make NT-proBNP accessible in clinical practice, it is essential to personalize and consider the whole context, such as age, sex, the presence of AF, renal failure and diastolic dysfunction ,44. SeveThe current study has some limitations related to the recruitment of the sample from a single center. Additional investigations of NT-proBNP and Galectin-3 levels were only performed at enrollment and were not repeated afterward by the investigators involved in the current study. Further research on a larger population and with an extended period of follow-up is needed to confirm the results of the current study. Patients were considered asymptomatic based on clinical judgment, and no exercises were performed due to the inability of this population to adapt to the treadmill.This research confirms the need to establish the optimal cutoff point of circulating biomarkers, as well as to determine its incremental value over other risk stratification methods. In our study, only NT-proBNP was a predictor of events in patients with asymptomatic severe AS. Moreover, a combination of both biomarkers may be a potential tool for the clinical follow-up of the elderly population with AS. Although Galectin-3 was moderately correlated with the echocardiographic parameters, its role as a predictor of MACEs was not confirmed. The proper use of biomarkers in clinical practice could prevent the irreversible and severe consequences that result from late surgical intervention.


The HYPEDIA study aimed at evaluating the implementation of the 2018 European guidelines for treating hypertension in primary care. A nationwide prospective non-interventional cross-sectional study was performed in consecutive untreated or treated hypertensives recruited mainly in primary care in Greece. Participants’ characteristics, office blood pressure (BP)  and treatment changes were recorded on a cloud platform. A total of 3,122 patients  were assessed by 181 doctors and 3 hospital centers. In 772 untreated hypertensives (25%), drug treatment was initiated in the majority, with monotherapy in 53.4%, two-drug combination in 36.3%, and three drugs in 10.3%. Angiotensin receptor blocker (ARB) monotherapy was initiated in 30%, ARB/calcium channel blocker (CCB) 20%, ARB/thiazide 8%, angiotensin converting enzyme inhibitor (ACEi)-based 19%. Of the combinations used, 97% were in single-pill. Among 977 treated hypertensives aged <65 years, 79% had BP ≥ 130/80 mmHg (systolic and/or diastolic), whereas among 1,373 aged ≥65 years, 66% had BP ≥ 140/80 mmHg. ARBs were used in 69% of treated hypertensives, CCBs 47%, ACEis 19%, diuretics 39%, beta-blockers 19%. Treatment modification was decided in 53% of treated hypertensives aged <65 years with BP ≥ 130/80 mmHg and in 62% of those ≥65 years with BP ≥ 140/80 mmHg. Renin-angiotensin system blocker-based therapy constitutes the basis of antihypertensive drug treatment in most patients in primary care, with wide use of single-pill combinations. In almost half of treated uncontrolled hypertensives, treatment was not intensified, suggesting suboptimal implementation of the guidelines and possible physician inertia. Arterial hypertension is a major global public health problem due to its high prevalence in the general population and its association with considerable cardiovascular morbidity and mortality . The benDespite the proven benefit of the antihypertensive treatment, hypertension awareness and BP control rates have remained poor worldwide , 3–6. ThOffice BP measurement has been regarded as the “cornerstone” for diagnosis and management of hypertension, because the vast majority of the evidence on the risks associated with elevated BP and the benefits of treatment-induced BP lowering has been based on office BP measurements , 8, 9. DAs hypertension affects more than one third of the adult population, most of these patients are managed in primary care. Real-life data on hypertension control rates in primary care setting demonstrate an evidence practice gap which is multifactorial and mainly attributed to poor patients’ compliance, physician inertia, and issues within the healthcare system services such as patient access and treatment costs , 5, 6. TThis was a national level, non-interventional, observational, cross-sectional, epidemiological study conducted in a single visit for each participant. The study was carried out between September 2019 and April 2020.This study was designed to assess doctor’s practices in the management of hypertension and to determine whether these practices adhere to the 2018 ESC/ESH recommendations.Fully ambulatory patients aged ≥18 years, diagnosed with essential hypertension at the time of enrolment were eligible for inclusion. Primary care sites and hospital centers were selected on the basis of distribution criteria so as to cover several territories throughout the country, and aiming to include hypertensive patients from different geographical regions of Greece. All the candidate sites were invited and informed by phone calls and/or emails. Each primary care investigator and each hospital clinic was asked to recruit at least 15 sequential patients of whom 25% naïve to treatment and 75% previously treated.Medical history, drug treatment, BP measurements and intended changes were recorded for each participant in a single visit using an electronic patient’s form of an online cloud platform. This electronic form was identified by a code assigned exclusively to each participant and was filled in during the study visit. Triplicate office BP measurements were taken after 5 min sitting rest at a chair with back support at 1-minute intervals, with the arm resting on a table (mid-arm at heart level) and feet flat on the floor. BP measurements were performed using a validated automated oscillometric, upper-arm BP monitor , equipped with a medium-large size cuff (wide range 22–42 cm) . BP readThe study protocol was approved by the Scientific/Ethics Committee of the Sotiria Hospital , General Hospital of Larissa (Greece), and Venizeleio General Hospital of Crete (Greece). All participants signed written informed consent for their participation in the study.The Kolmogorov–Smirnov test was used to check the normal distribution of the study variables. Continuous variables were expressed as mean (SD). Comparison of qualitative variables between 2 groups  was performed using Chi-squared or Fisher’s exact test. Comparison of quantitative variables between 2 groups was performed using the t-test or Mann-Whitney test based on normal or non-normal distribution respectively. Binary logistic regression analysis was applied to identify determinants of uncontrolled hypertension among treated patients. Independent variables included the setting of care , and factors related to patients’ characteristics . Non-parametric values were natural log-transformed before being used in the above analysis. Statistical analysis was performed using the IBM SPSS Statistics . A p-value lower than 0.05 was considered statistically significant.p = NS vs primary care) in 3 hospital centers. The study participants’ characteristics are shown in Table Overall, a total of 3122 patients were enrolled, of whom 3002 (25% untreated) were recruited by 181 primary care doctors and 120 , mean systolic/diastolic BP was 149.7 ± 18.1/89.0 ± 11.6 mmHg. Drug treatment was initiated in 769 patients with drug monotherapy in 53.4%, two-drug combination in 36.3%, and three drugs in 10.3%. There were 3 primary care doctors who initiated triple-drug therapy in 80–100% of their patients. Main choices for treatment initiation included angiotensin receptor blocker (ARB) monotherapy in 30%, ARB/calcium channel blocker (CCB) 20%, ARB/thiazide 8%, angiotensin-converting enzyme inhibitor (ACEi) monotherapy 11%, ACEi/CCB 4%, ACEi/thiazide (or thiazide-like) 1%, CCB monotherapy 5% and beta-blocker monotherapy 7% of the cases ,In 329 untreated patients aged <80 years with systolic BP ≥ 150 mmHg, treatment was initiated with drug monotherapy in 32%, two-drug combination in 50%, and three drugs in 18%.In 2350 treated hypertensives , mean systolic/diastolic BP was 140.2 ± 19.1/82.1 ± 11.8 mmHg. Mean duration of hypertension since initial diagnosis was 8.6 ± 6.9 years and treatment included on average 2.0 ± 0.9 antihypertensive drugs. Main drug classes administered in these patients were ARB monotherapy 18%, ARB/CCB 15%, ARB/thiazide 12%, ARB/CCB/thiazide 12%, ACEi monotherapy 7%, ACEi/CCB 4%, ACEi/thiazide (or thiazide-like) 3%, ACEi/CCB/thiazide-like 2%, CCB monotherapy 5%, beta-blocker monotherapy 4%, and other choices 18%. Single pill combinations were used in 85% of patients receiving combination therapy.N = 977), 79% had BP ≥ 130/80 mmHg (systolic and/or diastolic), whereas among those aged ≥65 years (N = 1373) 66% had BP ≥ 140/80 mmHg , showed that natural logarithm of BMI , and male versus female sex , were associated with a higher probability of uncontrolled hypertension.p = 0.06 for difference), whereas for diastolic BP target <80 mmHg 58% and 55% respectively (p = NS). For patients aged ≥65 years, 98% of primary care and 100% of hospital doctors used a systolic BP target <140 mmHg (p = NS), whereas for diastolic BP target <80 mmHg 61% and 51%, respectively (p = NS).For patients aged <65 years, 70% of primary care and 82% of hospital doctors used a systolic BP target <130 mmHg  Renin-angiotensin system blockers constitute the basis of antihypertensive treatment, mainly in single-pill two-drug combinations; (ii) in a considerable proportion of newly diagnosed untreated patients, treatment was initiated with monotherapy; (iii) more than half of treated patients had uncontrolled BP; (iv) treatment modification was decided in only about half of treated patients with uncontrolled BP.Renin-angiotensin system blockers  are recommended in the first step of the 2018 ESC/ESH treatment algorithm . Second,Another interesting finding is the relatively frequent use of drug monotherapy for treatment initiation in newly diagnosed hypertensive patients. These data are somewhat in contrast to the 2018 ESC/ESH strategy recommending two-drug combination therapy at first step for most patients aged <80 years with systolic BP ≥ 150 mmHg [A large proportion of treated patients in the current study presented with uncontrolled hypertension based on office BP, thus failing to reach the ESC/ESH recommended BP targets. It is also important to note that demographic characteristics such as male sex and higher BMI, which add cardiovascular risk, were associated with higher probability of uncontrolled hypertension. Although the ESC/ESH guidelines emphasize the important role of out-of-office BP measurements in the management of hypertension, reality is that in many patients in primary care the management of hypertension is based solely on office BP. Moreover, the 2018 ESC/ESH guidelines recommend a stricter BP target goal for patients <65 years (<130/80 mmHg) [When interpreting the findings of the current study it should be taken into consideration that BP was assessed in single office visit and out-of-office BP was not evaluated. Yet, in real life general practice, office BP measurements, usually under poorly defined conditions, may constitute the sole BP assessment method for many hypertensives considering the lack of time and resources in primary care. In addition, the doctors might have been influenced by (i) their participation in the study, which may have improved their compliance to the guidelines, and (ii) the fact that they were forced to take triplicate BP measurements  which may lead to more standardized office BP assessment compared to the usual care measurements. However, the study findings suggesting physician inertia indicate that the true behavior of physicians in clinical practice has been revealed to a large extent.In conclusion, renin-angiotensin system blocker-based therapy, mainly ARBs, constitutes the basis of antihypertensive drug treatment in the vast majority of patients in primary care, with single-pill combinations being widely used. In almost half of treated uncontrolled hypertensives treatment was not intensified (physician inertia), suggesting suboptimal implementation of the 2018 ESC/ESH goals in primary care. These findings support the need of reinforcing information and education strategies for primary care doctors so as to perform standardized BP measurements, detect hypertensive patients of high cardiovascular risk and implement early, more intense and simplified therapy through wider use of double and triple fixed-dose combinations, in line with the recommendations. Thus, it is highly important that both doctors and patients are informed about the evidence-based safety and benefits of the antihypertensive treatment strategy according to current guidelines, the need of accurate diagnosis, and the importance of achieving optimal control of BP in terms of more efficient cardiovascular disease prevention.Previous studies have confirmed poor control rates of treated hypertension in primary care worldwide.2018 ESH/ESC guidelines for the management of hypertension recommended a stepwise treatment algorithm with the use of single-pill combinations and stricter blood pressure targets than previous guidelines.In a large sample of hypertensive patients in primary care the implementation of the 2018 ESH/ESC guidelines for the management of hypertension was found to be suboptimal.Initial drug monotherapy, instead of drug combination, was decided for a considerable proportion of newly treated hypertensives.In almost half of treated uncontrolled hypertensives, treatment was not intensified, suggesting physician inertia.


Early computed tomography perfusion (CTP) is frequently used to predict delayed cerebral ischemia following aneurysmatic subarachnoid hemorrhage (aSAH). However, the influence of blood pressure on CTP is currently controversial , which differs from our clinical observations. Therefore, we aimed to investigate the influence of blood pressure on early CTP imaging in patients with aSAH.We retrospectively analyzed the mean transit time (MTT) of early CTP imaging within 24 h after bleeding prior to aneurysm occlusion with respect to blood pressure shortly before or after the examination in 134 patients. We correlated the cerebral blood flow with the cerebral perfusion pressure in the case of patients with intracranial pressure measurement. We performed a subgroup analysis of good-grade , poor-grade (WFNS IV–V), and solely WFNS grade V aSAH patients.R =  − 0.18, 95% confidence interval [CI] − 0.34 to − 0.01, p = 0.042). Lower mean blood pressure was significantly associated with a higher mean MTT. Subgroup analysis revealed an increasing inverse correlation when comparing WFNS I–III  patients with WFNS IV–V  patients, without reaching statistical significance. However, if only patients with WFNS V are considered, a significant and even stronger correlation between MAP and MTT  is observed. In patients with intracranial pressure monitoring, a stronger dependency of cerebral blood flow on cerebral perfusion pressure is observed for poor-grade patients compared with good-grade patients.Mean arterial pressure (MAP) significantly correlated inversely with the mean MTT in early CTP imaging (The inverse correlation between MAP and MTT in early CTP imaging, increasing with the severity of aSAH, suggests an increasing disturbance of cerebral autoregulation with the severity of early brain injury. Our results emphasize the importance of maintaining physiological blood pressure values in the early phase of aSAH and preventing hypotension, especially in patients with poor-grade aSAH.The online version contains supplementary material available at 10.1007/s12028-023-01683-8. In the past years, research into aneurysmal subarachnoid hemorrhage (aSAH) has been focused on the phase of delayed brain ischemia (DCI), with the occurrence of vasospasm as the most prominent pathophysiological correlate . RecentlWe hypothesize that the mean arterial pressure (MAP), possibly depending on the severity of SAH, correlates especially with the MTT in early perfusion imaging and that higher MAP is associated with shorter MTT, indicating better cerebral perfusion.All procedures were in accordance with the ethical standards of the institutional committee and with the 1964 Helsinki declaration and its later amendments. For this type of study, written formal consent was not required. The local ethics committee approved the study (study ID: 5760R). Data will be made available on reasonable request. We prepared the article according to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.A retrospective cohort study was performed for all patients with aSAH admitted to our tertiary neurovascular center from 2010 to 2015. The following inclusion criteria were applied: (1) SAH documented by an initial nonenhanced CT, (2) CTP imaging within 24 h after admission, and (3) documented blood pressure values within, at most, 60 min before or after the CT measurement. Patients were excluded from the study based on the following criteria: nonaneurysmal SAHs and unknown onset of aSAH (determined by self-reported time of the headache event or third-party report of sudden neurologic deterioration or unconsciousness). If a prolonged headache was present or the time of bleeding could not be determined with certainty, the patients were excluded from the analysis as well as patients with unevaluable early CTP imaging , patients with pretreated aneurysms or recurrent SAH at the time of early CT imaging, patients with a history of previous cranial neurosurgical or endovascular intervention, and patients with recorded mean blood pressure < 30 mmHg or > 130 mmHg at the time of interest.The remaining patients were initially dichotomized for subgroup analysis based on World Federation of Neurosurgical Societies (WFNS) grade (I–III vs. IV–V). Additionally, patients with WFNS grade V were evaluated separately to map only the most severe hemorrhages. For each patient, the average MTT was calculated from the early CT perfusion and analyzed for correlation with the recorded MAP value. According to the common model of cerebral autoregulation, further evaluation of CBF versus cerebral perfusion pressure (CPP) was performed for patients with external ventricular drainage (EVD) or intracranial pressure probe at the time of blood pressure recording.If an in-house native CT scan showed evidence of an aSAH, supplemental CT angiography and perfusion imaging were performed immediately in the same session. Patients in a peripheral hospital with evidence of SAH in a native CT scan and suspected aneurysm were transferred to our neurovascular center as soon as possible. They received CTP and CT angiography promptly on arrival. Treatment of patients with SAH in the early phase after hemorrhage was based on an in-house guideline following the applicable SAH guidelines . In all Computed tomography perfusion scans within 24 h after hemorrhage and before aneurysm repair were considered as early CTP imaging. CTP was performed as previously described: CTP data were acquired with a multislice CT scanner  , 11, 25.Vital parameters, such as blood pressure, are automatically documented and digitally stored with time stamps accurate to the second whenever a patient is connected to a stationary monitoring unit in either our emergency trauma room or neurosurgical intensive care unit. The blood pressure measurement is either a noninvasive measurement using an adequately sized blood pressure cuff on one of the upper arms or an invasive measurement from an arterial line  with the transducer positioned at heart level. The emergency trauma room of our tertiary care facility is equipped with a CT scanner capable of perfusion imaging, which allows for brief time intervals between blood pressure measurements and CTP imaging in primarily admitted patients.If the patient was primarily admitted to a peripheral hospital, the patient was directly transferred to our neurosurgical intensive care unit. The aforementioned system documents no values during patient transport to the CT. Blood pressure values recorded directly before or after transport were recorded and checked individually for plausibility. Of these two values, the single blood pressure value used for analysis was the one that was closer in time to the CTP imaging. If the pretransport and post-transport blood pressure values had the same time interval to CTP imaging, the pretransport values were preferred, as these were considered less susceptible to interference. Systolic, diastolic, MAP (MAP = diastolic + 1/3 [systolic-diastolic]), and CPP (if available) values with the shortest time interval to the CTP imaging were extracted from the database for evaluation.t-test was used to compare the mean of two groups. The significance level was set to 0.05. Dependency between CPP and CBF was modeled using linear regression.Patients’ characteristics and clinical data were analyzed using RStudio, Version 1.3.1093 and Python Version 3.9.7. Our primary aim was to analyze the correlation of cerebral perfusion and blood pressure early after SAH. To achieve this, we calculated the average MTT over the whole cortex from the early CTP for each patient and correlated it with the recorded MAP by using the Pearson correlation coefficient, as the data are interval scaled. Normal distribution and the assumption of linearity were established by plotting the data in a histogram and scatter plot, respectively. Correlation between mean MTT and WFNS, Fisher score, and mRS was tested using the Kendall rank correlation coefficient because ordinal items in each scale were equal to or less than 6, according to Khamis et al. . In the From the initial 702 patients with SAH during the study period, a total of 568 were excluded due to various factors, including those with missing pretreatment early CTP imaging, unknown onset of SAH, known history of cranial neurosurgical intervention or, in most cases, lack of timely blood pressure recording in relation to the time of CTP imaging. Thus, after applying the inclusion and exclusion criteria, 134 patients were included in the analysis. Patients’ characteristics distinguished by subgroup are depicted in Table p = 0.02), but not for diastolic  and mean blood pressure  when comparing patients with WFNS I–III versus patients with WFNS IV–V  and mean , but not in diastolic blood pressure : 65 ± 19) for all patients, 91 mm Hg  for patients with WFNS I–III, 84 mm Hg  for patients with WFNS IV–V and 81 mm Hg  in the subgroup including only patients with WFNS V. In the subgroup comparison, there was a significant difference for systolic  for all patients, 9 min (mean = 5.8 ± 22 min) for patients with WFNS I–III, 9 min (mean = 5.8 ± 25 min) for patients with WFNS IV–V, and 5.5 min (mean = 3.3 ± 23 min) for patients with WFNS V.p = 0.04), whereas the difference between WFNS grade I–III patients versus WFNS V patients was not significant  for all patients, 3.8 s (± 1.2) for patients with WFNS I–III, 4.2 s (± 1.2) for patients with WFNS IV–V, and 4 s (± 1.2) for patients with WFNS V. The difference between patients with WFNS grade I–III vs. WFNS grade IV–V was significant , the mRS at discharge ([T] = 0.19 p < 0.01), and the mRS after 6 months ([T] = 0.17 p < 0.01), but not with the Fisher grade ([T] = 0.06 p = 0.37).The MTT of early CTP in the whole study population significantly correlated with the initial WFNS  was observed  was observed , with R =  − 0.2  should also be taken into account, although in our study, this positional change most likely affects all patients to the same extent . FurtherPatients with an inserted EVD are, in most cases, sedated and often also ventilated. The influence of sedation on the result of this study cannot be ruled out. Yet, an influence of the intracranial pressure on the results of the study is considered unlikely. Patients without EVD are conscious and a normal intracranial pressure can therefore be assumed, and in patients with EVD the intracranial pressure is normalized to a physiological level. Further subgroup analysis of dichotomized subgroups of patients with versus without EVD at the imaging time is attached in the supplementary material.Data from CTP imaging are difficult to compare one-to-one between different setups due to different CTP protocols and postprocessing. In addition, diseases affecting the microvasculature such as atheriosclerosis, hypertension, or diabetes may influence the MTT. Additionally, metabolic state, use of sedatives, and concomitant medication may potentially impact the MTT, as well. Therefore, the effect of these factors on the results of this study remains unclear. Furthermore, it is unclear whether there are differences in the MTT when blood pressure values are present spontaneously or are influenced by medication. Similarly, it is not clear whether mean MTT alone or a combination of different parameters of CTP best represents the relevant pathophysiological changes in patients with aSAH, which should be taken into account when interpreting the data.Some study limitations are worth noting:In the present cohort of 134 patients with aSAH, MTT of early CTP inversely correlates with the MAP, indicating early impairment of cerebral autoregulation in the phase of EBI. A low MAP is associated with a prolonged MTT. The subgroup analysis shows that the inverse correlation becomes stronger with the severity of aSAH as measured by the WFNS, whereas, in particular, WFNS grade V patients demonstrated a significant, strong, inverse correlation of MAP and MTT.These results emphasize the importance of maintaining physiological blood pressure values in the EBI phase and preventing hypotension, especially in patients with poor-grade aSAH. Further prospective studies should seek to confirm this influence of MAP on MTT in EBI and should verify whether the early blood pressure values correlate with the outcome of the patients post aSAH.Supplementary file1 (PDF 210 KB)Below is the link to the electronic supplementary material.