Reduced uterine perfusion pressure as a model for preeclampsia and fetal growth restriction in murine: a systematic review and meta-analysis.

The reduced uterine perfusion pressure (RUPP) model is frequently used to study preeclampsia and fetal growth restriction. An improved understanding of influential factors might improve reproducibility and reduce animal use considering the variability in RUPP phenotype. We performed a systematic review and meta-analysis by searching Medline and Embase (until 28 March, 2023) for RUPP studies in murine. Primary outcomes included maternal blood pressure (BP) or proteinuria, fetal weight or crown-rump length, fetal reabsorptions, or antiangiogenic factors. We aimed to identify influential factors by meta-regression analysis. We included 155 studies. Our meta-analysis showed that the RUPP procedure results in significantly higher BP (MD = 24.1 mmHg; [22.6; 25.7]; n = 148), proteinuria (SMD = 2.3; [0.9; 3.8]; n = 28), fetal reabsorptions (MD = 50.4%; [45.5; 55.2]; n = 42), circulating soluble FMS-like tyrosine kinase-1 (sFlt-1) (SMD = 2.6; [1.7; 3.4]; n = 34), and lower fetal weight (MD = -0.4 g; [-0.47; -0.34]; n = 113. The heterogeneity (variability between studies) in primary outcomes appeared ≥90%. Our meta-regression identified influential factors in the method and time point of BP measurement, randomization in fetal weight, and type of control group in sFlt-1. The RUPP is a robust model considering the evident differences in maternal and fetal outcomes. The high heterogeneity reflects the observed variability in phenotype. Because of underreporting, we observed reporting bias and a high risk of bias. We recommend standardizing study design by optimal time point and method chosen for readout measures to limit the variability. This contributes to improved reproducibility and thereby eventually improves the translational value of the RUPP model.

Cerebral autoregulation in traumatic brain injury: ultra-low-frequency pressure reactivity index and intracranial pressure across age groups.

BACKGROUND: The ultra-low-frequency pressure reactivity index (UL-PRx) has been established as a surrogate method for bedside estimation of cerebral autoregulation (CA). Although this index has been shown to be a predictor of outcome in adult and pediatric patients with traumatic brain injury (TBI), a comprehensive evaluation of low sampling rate data collection (0.0033 Hz averaged over 5 min) on cerebrovascular reactivity has never been performed. OBJECTIVE: To evaluate the performance and predictive power of the UL-PRx for 12-month outcome measures, alongside all International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) models and in different age groups. To investigate the potential for optimal cerebral perfusion pressure (CPPopt). METHODS: Demographic data, IMPACT variables, in-hospital mortality, and Glasgow Outcome Scale Extended (GOSE) at 12 months were extracted. Filtering and processing of the time series and creation of the indices (cerebral intracranial pressure (ICP), cerebral perfusion pressure (CPP), UL-PRx, and deltaCPPopt (ΔCPPopt and CPPopt-CPP)) were performed using an in-house algorithm. Physiological parameters were assessed as follows: mean index value, % time above threshold, and mean hourly dose above threshold. RESULTS: A total of 263 TBI patients were included: pediatric (17.5% aged ≤ 16 y) and adult (60.5% aged > 16 and < 70 y and 22.0% ≥ 70 y, respectively) patients. In-hospital and 12-month mortality were 25.9% and 32.7%, respectively, and 60.0% of patients had an unfavorable outcome at 12 months (GOSE). On univariate analysis, ICP, CPP, UL-PRx, and ΔCPPopt were associated with 12-month outcomes. The cutoff of ~ 20-22 for mean ICP and of ~ 0.30 for mean UL-PRx were confirmed in all age groups, except in patients older than 70 years. Mean UL-PRx remained significantly associated with 12-month outcomes even after adjustment for IMPACT models. This association was confirmed in all age groups. UL-PRx resulted associate with CPPopt. CONCLUSIONS: The study highlights UL-PRx as a tool for assessing CA and valuable outcome predictor for TBI patients. The results emphasize the potential clinical utility of the UL-PRx and its adaptability across different age groups, even after adjustment for IMPACT models. Furthermore, the correlation between UL-PRx and CPPopt suggests the potential for more targeted treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05043545, principal investigator Paolo Gritti, date of registration 2021.08.21.

Monitoring of cerebral blood flow autoregulation: physiologic basis, measurement, and clinical implications.

Cerebral blood flow (CBF) autoregulation is the physiologic process whereby blood supply to the brain is kept constant over a range of cerebral perfusion pressures ensuring a constant supply of metabolic substrate. Clinical methods for monitoring CBF autoregulation were first developed for neurocritically ill patients and have been extended to surgical patients. These methods are based on measuring the relationship between cerebral perfusion pressure and surrogates of CBF or cerebral blood volume (CBV) at low frequencies (<0.05 Hz) of autoregulation using time or frequency domain analyses. Initially intracranial pressure monitoring or transcranial Doppler assessment of CBF velocity was utilised relative to changes in cerebral perfusion pressure or mean arterial pressure. A more clinically practical approach utilising filtered signals from near infrared spectroscopy monitors as an estimate of CBF has been validated. In contrast to the traditional teaching that 50 mm Hg is the autoregulation threshold, these investigations have found wide interindividual variability of the lower limit of autoregulation ranging from 40 to 90 mm Hg in adults and 20-55 mm Hg in children. Observational data have linked impaired CBF autoregulation metrics to adverse outcomes in patients with traumatic brain injury, ischaemic stroke, subarachnoid haemorrhage, intracerebral haemorrhage, and in surgical patients. CBF autoregulation monitoring has been described in both cardiac and noncardiac surgery. Data from a single-centre randomised study in adults found that targeting arterial pressure during cardiopulmonary bypass to above the lower limit of autoregulation led to a reduction of postoperative delirium and improved memory 1 month after surgery compared with usual care. Together, the growing body of evidence suggests that monitoring CBF autoregulation provides prognostic information on eventual patient outcomes and offers potential for therapeutic intervention. For surgical patients, personalised blood pressure management based on CBF autoregulation data holds promise as a strategy to improve patient neurocognitive outcomes.

Individualized Autoregulation-Derived Cerebral Perfusion Targets in Aneurysmal Subarachnoid Hemorrhage: A New Therapeutic Avenue?

Background: Cerebral perfusion pressure (CPP) is an important target in aneurysmal subarachnoid hemorrhage (aSAH), but it does not take into account autoregulatory disturbances. The pressure reactivity index (PRx) and the CPP with the optimal PRx (CPPopt) are new variables that may capture these pathomechanisms. In this study, we investigated the effect on the outcome of certain combinations of CPP or ΔCPPopt (actual CPP-CPPopt) with the concurrent autoregulatory status (PRx) after aSAH. Methods: This observational study included 432 aSAH patients, treated in the neurointensive care unit, at Uppsala University Hospital, Sweden. Functional outcome (GOS-E) was assessed 1-year postictus. Heatmaps of the percentage of good monitoring time (%GMT) of PRx/CPP and PRx/ΔCPPopt combinations in relation to GOS-E were created to visualize the association between these variables and outcome. Results: In the heatmap of the %GMT of PRx/CPP, the combination of lower CPP with higher PRx values was more strongly associated with lower GOS-E. The tolerance for lower CPP values increased with lower PRx values until a threshold of -0.50. However, for decreasing PRx below -0.50, there was a gradual reduction in the tolerance for lower CPP. In the heatmap of the %GMT of PRx/ΔCPPopt, the combination of negative ΔCPPopt with higher PRx values was strongly associated with lower GOS-E. In particular, negative ΔCPPopt together with PRx above +0.50 correlated with worse outcomes. In addition, there was a transition toward an unfavorable outcome when PRx went below -0.50, particularly if ΔCPPopt was negative. Conclusions: The PRx levels influenced the association between CPP/ΔCPPopt and outcome. Thus, this variable could be used to individualize a safe CPP-/ΔCPPopt-range.

The prediction of estimated cerebral perfusion pressure with trans-systolic time in preterm and term infants.

It is important to monitor cerebral perfusion in infants because hypo- and hyperperfusion can contribute to neurological injury. This study aimed to clarify the relationship between trans-systolic time (TST) and critical closing pressure (CrCP) or estimated cerebral perfusion pressure (CPPe) in neonates. Moreover, we aimed to determine the TST values in preterm and term infants with stable cerebral perfusion to clarify normative reference data. This multicentre prospective study included infants with arterial lines admitted to the neonatal intensive care units between December 2021 and August 2023. TST, CrCP, and CPPe were calculated using middle cerebral artery waveforms recorded using transcranial Doppler ultrasonography when clinicians collected arterial blood samples. Three hundred and sixty samples were obtained from 112 infants with a gestational age of 32 (interquartile range, 27-37) weeks and a birth weight of 1481 (956-2355) g. TST was positively correlated with CPPe (r = 0.60, p < 0.001), but not with CrCP (r = 0.08, p = 0.10). The normative reference values of TST in preterm and term infants without samples of hyper- or hypocapnia and/or hyper- or hypotension, which may affect cerebral perfusion, were as follows: ≤ 29 weeks, 0.12 (0.11-0.14) s; 30-36 weeks, 0.14 (0.12-0.15) s; and ≥ 37 weeks, 0.16 (0.14-0.17) s, respectively.  Conclusion: TST in neonates significantly correlated with CPPe, but not with CrCP. TST may be a good predictor of cerebral perfusion and potentially have wider clinical applications. What is Known: • Trans-systolic time (TST) is used in evaluating the effects of increased intracranial pressure on cerebral haemodynamics. However, little is known about the efficacy of TST in predicting neonatal cerebral perfusion pressure. What is New: • This study added evidence that TST correlated with estimated cerebral perfusion pressure, but not with critical closing pressure. Additionally, we showed the normative reference values of the TST in preterm and term infants.

Associations of long-term fluctuation in blood pressure and ocular perfusion pressure with visual field progression in normal-tension glaucoma.

BACKGROUD: The aim of this study was to investigate the associations between fluctuation in blood pressure (BP), ocular perfusion pressure (OPP) and visual field (VF) progression in normal-tension glaucoma (NTG). METHODS: This prospective, longitudinal study included 44 patients with NTG. Only newly diagnosed NTG patients who had not been treated with a glaucoma medication were included. Patients were examined every year for 7 years. Intraocular pressure (IOP), heart rate (HR), systolic BP (SBP), diastolic BP (DBP), ocular perfusion pressure (OPP), and diastolic ocular perfusion pressure (DOPP) were measured at the same time. Ophthalmic examinations, including perimetry, were performed also. Initial VF were compared with follow-up data after 7 years. RESULTS: After 7 years of follow-up, 9 of the 44 patients showed VF progression. The standard deviation (SD) of SBP and OPP were significantly associated with VF progression (P = 0.007, < 0.001, respectively). Multiple regression analysis showed that VF progression was significantly associated with SD of OPP (odds ratio, OR = 2.012, 95% CI = 1.016-3.985; P = 0.045). CONCLUSIONS: Fluctuation in OPP was associated with VF progression in patients with NTG.

Transmission of high arterial pressure into renal microvessels during venous-clamping augments ischaemia/reperfusion-induced acute kidney injury in anaesthetized rats.

AIM: In two recent studies, we observed that a 30-min renal vein clamping caused formation of interstitial haemorrhagic congestion in ischaemic and ischaemic/reperfused kidney along with the development of severer acute kidney injury (AKI) than renal artery or pedicle clamping. It was suggested that the transmission of high arterial pressure into renal microvessels during vein occlusion probably causes the occurrence of interstitial haemorrhagic congestion that augments AKI. The present investigation aimed to evaluate this suggestion by reducing renal perfusion pressure (RPP) during renal venous occlusion. METHODS: Anaesthetized male Sprague-Dawley rats were divided into three groups (n = 8), which underwent a 2-h reperfusion period following 30-min bilateral renal venous clamping along with reduced RPP (VIR-rRPP group) or without reduced RPP (VIR group) and an equivalent period after sham-operation (Sham group). RESULTS: The VIR-rRPP group compared with VIR group had lower levels of kidney malondialdehyde and tissue damages as epithelial injuries of proximal tubule and thick ascending limb, vascular congestion, intratubular cast and oedema, along with the less reductions in renal blood flow, creatinine clearance, Na+ -reabsorption, K+ and urea excretion, urine osmolality and free-water reabsorption. Importantly, the formation of intensive interstitial haemorrhagic congestion in the VIR group was not observed in the VIR-rRPP group. CONCLUSION: These results indicate that the transmission of high arterial pressure into renal microvessels during venous occlusion leads to rupturing of their walls and the formation of interstitial haemorrhagic congestion, which has an augmenting impact on ischaemia/reperfusion-induced renal structural damages and haemodynamic, excretory and urine-concentrating dysfunctions.

Brain tissue oxygen partial pressure monitoring and prognosis of patients with traumatic brain injury: a meta-analysis.

To assess whether monitoring brain tissue oxygen partial pressure (PbtO2) or employing intracranial pressure (ICP)/cerebral perfusion pressure (CCP)-guided management improves patient outcomes, including mortality, hospital length of stay (LOS), mean daily ICP and mean daily CCP during the intensive care unit(ICU)stay. We searched the Web of Science, EMBASE, PubMed, Cochrane Library, and MEDLINE databases until December 12, 2023. Prospective randomized controlled and cohort studies were included. A meta-analysis was performed for the primary outcome measure, mortality, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eleven studies with a total of 37,492 patients were included. The mortality in the group with PbtO2 was 29.0% (odds ratio: 0.73;95% confidence interval [CI]:0.56-0.96; P = 0.03; I = 55%), demonstrating a significant benefit. The overall hospital LOS was longer in the PbtO2 group than that in the ICP/CPP group (mean difference:2.03; 95% CI:1.03-3.02; P<0.0001; I = 39%). The mean daily ICP in the PbtO2 monitoring group was lower than that in the ICP/CPP group (mean difference:-1.93; 95% CI: -3.61 to -0.24; P = 0.03; I = 41%). Moreover, PbtO2 monitoring did not improve the mean daily CPP (mean difference:2.43; 95%CI: -1.39 to 6.25;P = 0.21; I = 56%).Compared with ICP/CPP monitoring, PbtO2 monitoring reduced the mortality and the mean daily ICP in patients with severe traumatic brain injury; however, no significant effect was noted on the mean daily CPP. In contrast, ICP/CPP monitoring alone was associated with a short hospital stay.

MicroRNA-195-5p Attenuates Pregnancy-Induced Hypertension by Inhibiting Oxidative Stress via OTX1/MAPK Signaling Pathway.

Pregnancy-induced hypertension (PIH) is a hypertensive disorder during pregnancy and can induce perinatal death of human infants. MicroRNA (miR)-195-5p was validated to display low expression in severe preeclampsia placentas, but the role of miR-195-5p in pregnancy-induced hypertension (PIH) has not been investigated. The study emphasized on the functions and mechanism of miR-195-5p in PIH. A reduced uterine perfusion pressure (RUPP) rat model was established to mimic PIH in vivo. Adenovirus (Ad)-miR-195-5p agomir and/or Ad-OTX1 were further injected into some model rats. RT-qPCR was conducted to assess the expression of miR-195-5p and orthodenticle homeobox 1 (OTX1) in rat placental tissues, the isolated aortic endothelial cells (AECs), and in serum samples of PIH patients. Western blot analysis was implemented to measure the protein levels of OTX1, VEGFA, and key factors involved in the MAPK signaling pathway. The concentrations of oxidative stress markers (superoxide dismutase, catalase, and lipid hydroperoxide) in AECs and placental tissues of RUPP rats were measured by corresponding kits. The binding relation between miR-195-5p and OTX1 was verified using the dual-luciferase reporter assay. Hematoxylin-eosin staining was conducted to evaluate the pathological features of rat placental tissues. MiR-195-5p was downregulated, while OTX1 was upregulated in rat placental tissues and human serum samples of PIH patients. MiR-195-5p could target OTX1 and inversely regulate OTX1 expression in AECs and rat placental tissues. In addition, miR-195-5p can negatively regulate VEGFA level. Furthermore, miR-195-5p inactivates oxidative stress and the MAPK signaling by downregulating OTX1 in AECs. In vivo experiments revealed that OTX1 overexpression reversed the protective effect of miR-195-5p overexpression on placental damage and oxidative stress. MiR-195-5p alleviates PIH by inhibiting oxidative stress via targeting OTX1 and inactivating MAPK signaling.

The effects of cerebral pressure autoregulation status and CPP levels on cerebral metabolism in pediatric traumatic brain injury.

BACKGROUND: Cerebral perfusion pressure (CPP) management in the developing child with traumatic brain injury (TBI) is challenging. The pressure reactivity index (PRx) may serve as marker of cerebral pressure autoregulation (CPA) and optimal CPP (CPPopt) may be assessed by identifying the CPP level with best (lowest) PRx. To evaluate the potential of CPPopt guided management in children with severe TBI, cerebral microdialysis (CMD) monitoring levels of lactate and the lactate/pyruvate ratio (LPR) (indicators of ischemia) were related to actual CPP levels, autoregulatory state (PRx) and deviations from CPPopt (ΔCPPopt). METHODS: Retrospective study of 21 children ≤ 17 years with severe TBI who had both ICP and CMD monitoring were included. CPP, PRx, CPPopt and ΔCPPopt where calculated, dichotomized and compared with CMD lactate and lactate-pyruvate ratio. RESULTS: Median age was 16 years (range 8-17) and median Glasgow coma scale motor score 5 (range 2-5). Both lactate (p = 0.010) and LPR (p = < 0.001) were higher when CPP ≥ 70 mmHg than when CPP < 70. When PRx ≥ 0.1 both lactate and LPR were higher than when PRx < 0.1 (p = < 0.001). LPR was lower (p = 0.012) when CPPopt ≥ 70 mmHg than when CPPopt < 70, but there were no differences in lactate levels. When ΔCPPopt > 10 both lactate (p = 0.026) and LPR (p = 0.002) were higher than when ΔCPPopt < -10. CONCLUSIONS: Increased levels of CMD lactate and LPR in children with severe TBI appears to be related to disturbed CPA (PRx). Increased lactate and LPR also seems to be associated with actual CPP levels ≥ 70 mmHg. However, higher lactate and LPR values were also seen when actual CPP was above CPPopt. Higher CPP appears harmful when CPP is above the upper limit of pressure autoregulation. The findings indicate that CPPopt guided CPP management may have potential in pediatric TBI.

Cerebrovascular reactivity (PRx) and optimal cerebral perfusion pressure in elderly with traumatic brain injury.

PURPOSE: Cerebral perfusion pressure (CPP) guidance by cerebral pressure autoregulation (CPA) status according to PRx (correlation mean arterial blood pressure (MAP) and intracranial pressure (ICP)) and optimal CPP (CPPopt = CPP with lowest PRx) is promising but little is known regarding this approach in elderly. The aim was to analyze PRx and CPPopt in elderly TBI patients. METHODS: A total of 129 old (≥ 65 years) and 342 young (16-64 years) patients were studied using monitoring data for MAP and ICP. CPP, PRx, CPPopt, and ΔCPPopt (difference between actual CPP and CPPopt) were calculated. Logistic regression analyses with PRx and ΔCPPopt as explanatory variables for outcome. The combined effects of PRx/CPP and PRx/ΔCPPopt on outcome were visualized as heatmaps. RESULTS: The elderly had higher PRx (worse CPA), higher CPPopt, and different temporal patterns. High PRx influenced outcome negatively in the elderly but less so than in younger patients. CPP close to CPPopt correlated to favorable outcome in younger, in contrast to elderly patients. Heatmap interaction analysis of PRx/ΔCPPopt in the elderly showed that the region for favorable outcome was centered around PRx 0 and ranging between both functioning and impaired CPA (PRx range - 0.5-0.5), and the center of ΔCPPopt was - 10 (range - 20-0), while in younger the center of PRx was around - 0.5 and ΔCPPopt closer to zero. CONCLUSIONS: The elderly exhibit higher PRx and CPPopt. High PRx influences outcome negatively in the elderly but less than in younger patients. The elderly do not show better outcome when CPP is close to CPPopt in contrast to younger patients.

Variations in Autoregulation-Based Optimal Cerebral Perfusion Pressure Determination Using Two Integrated Neuromonitoring Platforms in a Trauma Patient.

BACKGROUND: Neuromonitoring devices are often used in traumatic brain injury. The objective of this report is to raise awareness concerning variations in optimal cerebral perfusion pressure (CPPopt) determination using exploratory information provided by two neuromonitoring monitors that are part of research programs (Moberg CNS Monitor and RAUMED NeuroSmart LogO). METHODS: We connected both monitors simultaneously to a parenchymal intracranial pressure catheter and recorded the pressure reactivity index (PRx) and the derived CPPopt estimates for a patient with a severe traumatic brain injury. These estimates were available at the bedside and were updated at each minute. RESULTS: Using the Bland and Altman method, we found a mean variation of - 3.8 (95% confidence internal from - 8.5 to 0.9) mm Hg between the CPPopt estimates provided by the two monitors (limits of agreement from - 26.6 to 19.1 mm Hg). The PRx and CPPopt trends provided by the two monitors were similar over time, but CPPopt trends differed when PRx values were around zero. Also, almost half of the CPPopt estimates differed by more than 10 mm Hg. CONCLUSIONS: These wide variations recorded in the same patient are worrisome and reiterate the importance of understanding and standardizing the methodology and algorithms behind commercial neuromonitoring devices prior to incorporating them in clinical use.

Should Patients with Traumatic Brain Injury with Significant Contusions be Treated with Different Neurointensive Care Targets?

BACKGROUND: Patients with traumatic brain injury (TBI) with large contusions make up a specific TBI subtype. Because of the risk of brain edema worsening, elevated cerebral perfusion pressure (CPP) may be particularly dangerous. The pressure reactivity index (PRx) and optimal cerebral perfusion pressure (CPPopt) are new promising perfusion targets based on cerebral autoregulation, but they reflect the global brain state and may be less valid in patients with predominant focal lesions. In this study, we aimed to investigate if patients with TBI with significant contusions exhibited a different association between PRx, CPP, and CPPopt in relation to functional outcome compared to those with small/no contusions. METHODS: This observational study included 385 patients with moderate to severe TBI treated at a neurointensive care unit in Uppsala, Sweden. The patients were classified into two groups: (1) significant contusions (> 10 mL) and (2) small/no contusions (but with extra-axial or diffuse injuries). The percentage of good monitoring time (%GMT) with intracranial pressure > 20 mm Hg; PRx > 0.30; CPP < 60 mm Hg, within 60-70 mm Hg, or > 70 mm Hg; and ΔCPPopt less than - 5 mm Hg, ± 5 mm Hg, or > 5 mm Hg was calculated. Outcome (Glasgow Outcome Scale-Extended) was assessed after 6 months. RESULTS: Among the 120 (31%) patients with significant contusions, a lower %GMT with CPP between 60 and 70 mm Hg was independently associated with unfavorable outcome. The %GMTs with PRx and ΔCPPopt ± 5 mm Hg were not independently associated with outcome. Among the 265 (69%) patients with small/no contusions, a higher %GMT of PRx > 0.30 and a lower %GMT of ΔCPPopt ± 5 mm Hg were independently associated with unfavorable outcome. CONCLUSIONS: In patients with TBI with significant contusions, CPP within 60-70 mm Hg may improve outcome. PRx and CPPopt, which reflect global cerebral pressure autoregulation, may be useful in patients with TBI without significant focal brain lesions but seem less valid for those with large contusions. However, this was an observational, hypothesis-generating study; our findings need to be validated in prospective studies before translating them into clinical practice.

A Comprehensive Perspective on Intracranial Pressure Monitoring and Individualized Management in Neurocritical Care: Results of a Survey with Global Experts.

BACKGROUND: Numerous trials have addressed intracranial pressure (ICP) management in neurocritical care. However, identifying its harmful thresholds and controlling ICP remain challenging in terms of improving outcomes. Evidence suggests that an individualized approach is necessary for establishing tolerance limits for ICP, incorporating factors such as ICP waveform (ICPW) or pulse morphology along with additional data provided by other invasive (e.g., brain oximetry) and noninvasive monitoring (NIM) methods (e.g., transcranial Doppler, optic nerve sheath diameter ultrasound, and pupillometry). This study aims to assess current ICP monitoring practices among experienced clinicians and explore whether guidelines should incorporate ancillary parameters from NIM and ICPW in future updates. METHODS: We conducted a survey among experienced professionals involved in researching and managing patients with severe injury across low-middle-income countries (LMICs) and high-income countries (HICs). We sought their insights on ICP monitoring, particularly focusing on the impact of NIM and ICPW in various clinical scenarios. RESULTS: From October to December 2023, 109 professionals from the Americas and Europe participated in the survey, evenly distributed between LMIC and HIC. When ICP ranged from 22 to 25 mm Hg, 62.3% of respondents were open to considering additional information, such as ICPW and other monitoring techniques, before adjusting therapy intensity levels. Moreover, 77% of respondents were inclined to reassess patients with ICP in the 18-22 mm Hg range, potentially escalating therapy intensity levels with the support of ICPW and NIM. Differences emerged between LMIC and HIC participants, with more LMIC respondents preferring arterial blood pressure transducer leveling at the heart and endorsing the use of NIM techniques and ICPW as ancillary information. CONCLUSIONS: Experienced clinicians tend to personalize ICP management, emphasizing the importance of considering various monitoring techniques. ICPW and noninvasive techniques, particularly in LMIC settings, warrant further exploration and could potentially enhance individualized patient care. The study suggests updating guidelines to include these additional components for a more personalized approach to ICP management.

Continuous Monitoring of Cerebral Autoregulation in Adults Supported by Extracorporeal Membrane Oxygenation.

BACKGROUND: Impaired cerebral autoregulation (CA) is one of several proposed mechanisms of acute brain injury in patients supported by extracorporeal membrane oxygenation (ECMO). The primary aim of this study was to determine the feasibility of continuous CA monitoring in adult ECMO patients. Our secondary aims were to describe changes in cerebral oximetry index (COx) and other metrics of CA over time and in relation to functional neurologic outcomes. METHODS: This is a single-center prospective observational study. We measured COx, a surrogate measurement of cerebral blood flow measured by near-infrared spectroscopy, which is an index of CA derived from the moving correlation between mean arterial pressure (MAP) and slow waves of regional cerebral oxygen saturation. A COx value that approaches 1 indicates impaired CA. Using COx, we determined the optimal MAP (MAPOPT) and lower and upper limits of autoregulation for individual patients. These measurements were examined in relation to modified Rankin Scale (mRS) scores. RESULTS: Fifteen patients (median age 57 years [interquartile range 47-69]) with 150 autoregulation measurements were included for analysis. Eleven were on veno-arterial ECMO (VA-ECMO), and four were on veno-venous ECMO (VV-ECMO). Mean COx was higher on postcannulation day 1 than on day 2 (0.2 vs. 0.09, p < 0.01), indicating improved CA over time. COx was higher in VA-ECMO patients than in VV-ECMO patients (0.12 vs. 0.06, p = 0.04). Median MAPOPT for the entire cohort was highly variable, ranging from 55 to 110 mm Hg. Patients with mRS scores 0-3 (good outcome) at 3 and 6 months spent less time outside MAPOPT compared with patients with mRS scores 4-6 (poor outcome) (74% vs. 82%, p = 0.01). The percentage of time when observed MAP was outside the limits of autoregulation was higher on postcannulation day 1 than on day 2 (18.2% vs. 3.3%, p < 0.01). CONCLUSIONS: In ECMO patients, it is feasible to monitor CA continuously at the bedside. CA improved over time, most significantly between postcannulation days 1 and 2. CA was more impaired in VA-ECMO patients than in VV-ECMO patients. Spending less time outside MAPOPT may be associated with achieving a good neurologic outcome.

The Effects of Head Elevation on Intracranial Pressure, Cerebral Perfusion Pressure, and Cerebral Oxygenation Among Patients with Acute Brain Injury: A Systematic Review and Meta-Analysis.

BACKGROUND: Head elevation is recommended as a tier zero measure to decrease high intracranial pressure (ICP) in neurocritical patients. However, its quantitative effects on cerebral perfusion pressure (CPP), jugular bulb oxygen saturation (SjvO2), brain tissue partial pressure of oxygen (PbtO2), and arteriovenous difference of oxygen (AVDO2) are uncertain. Our objective was to evaluate the effects of head elevation on ICP, CPP, SjvO2, PbtO2, and AVDO2 among patients with acute brain injury. METHODS: We conducted a systematic review and meta-analysis on PubMed, Scopus, and Cochrane Library of studies comparing the effects of different degrees of head elevation on ICP, CPP, SjvO2, PbtO2, and AVDO2. RESULTS: A total of 25 articles were included in the systematic review. Of these, 16 provided quantitative data regarding outcomes of interest and underwent meta-analyses. The mean ICP of patients with acute brain injury was lower in group with 30° of head elevation than in the supine position group (mean difference [MD] - 5.58 mm Hg; 95% confidence interval [CI] - 6.74 to - 4.41 mm Hg; p < 0.00001). The only comparison in which a greater degree of head elevation did not significantly reduce the ICP was 45° vs. 30°. The mean CPP remained similar between 30° of head elevation and supine position (MD - 2.48 mm Hg; 95% CI - 5.69 to 0.73 mm Hg; p = 0.13). Similar findings were observed in all other comparisons. The mean SjvO2 was similar between the 30° of head elevation and supine position groups (MD 0.32%; 95% CI - 1.67% to 2.32%; p = 0.75), as was the mean PbtO2 (MD - 1.50 mm Hg; 95% CI - 4.62 to 1.62 mm Hg; p = 0.36), and the mean AVDO2 (MD 0.06 µmol/L; 95% CI - 0.20 to 0.32 µmol/L; p = 0.65).The mean ICP of patients with traumatic brain injury was also lower with 30° of head elevation when compared to the supine position. There was no difference in the mean values of mean arterial pressure, CPP, SjvO2, and PbtO2 between these groups. CONCLUSIONS: Increasing degrees of head elevation were associated, in general, with a lower ICP, whereas CPP and brain oxygenation parameters remained unchanged. The severe traumatic brain injury subanalysis found similar results.

Periods of low renal perfusion pressure are associated with acute kidney injury following paediatric cardiac surgery.

INTRODUCTION: Acute kidney injury is associated with worse outcomes after cardiac surgery. The haemodynamic goals to ameliorate kidney injury are not clear. Low post-operative renal perfusion pressure has been associated with acute kidney injury in adults. Inadequate oxygen delivery may also cause kidney injury. This study evaluates pressure and oximetric haemodynamics after paediatric cardiac surgery and their association with acute kidney injury. MATERIALS AND METHODS: Retrospective case-control study at a children's hospital. Patients were < 6 months of age who underwent a Society of Thoracic Surgery-European Association for Cardio-Thoracic Surgery Congenital Heart Surgery categories ≥ 3. Low renal perfusion pressure was time and depth below several tested thresholds. The primary outcome was serum creatine-defined acute kidney injury in the first 7 days. RESULTS: Sixty-six patients (median age 8 days) were included. Acute kidney injury occurred in 36%. The time and depth of renal perfusion pressure < 42 mmHg in the first 24 hours was greater in acute kidney injury patients (94 versus 35 mmHg*minutes of low renal perfusion pressure/hour, p = 0.008). In the multivariable model, renal perfusion pressure < 42 mmHg was associated with acute kidney injury (aOR: 2.07, 95%CI: 1.25-3.82, p = 0.009). Mean arterial pressure, central venous pressure, and measures of inadequate oxygen delivery were not associated with acute kidney injury. CONCLUSION: Periods of low renal perfusion pressure (<42 mmHg) in the first 24 post-operative hours are associated with acute kidney injury. Renal perfusion pressure is a potential modifiable target that may mitigate the impact of acute kidney injury after paediatric cardiac surgery.

Control of mean arterial pressure using a closed-loop system for norepinephrine infusion in severe brain injury patients: the COMAT randomized controlled trial.

Brain injury patients require precise blood pressure (BP) management to maintain cerebral perfusion pressure (CPP) and avoid intracranial hypertension. Nurses have many tasks and norepinephrine titration has been shown to be suboptimal. This can lead to limited BP control in patients that are in critical need of cerebral perfusion optimization. We have designed a closed-loop vasopressor (CLV) system capable of maintaining mean arterial pressure (MAP) in a narrow range and we aimed to assess its performance when treating severe brain injury patients. Within the first 48 h of intensive care unit (ICU) admission, 18 patients with a severe brain injury underwent either CLV or manual norepinephrine titration. In both groups, the objective was to maintain MAP in target (within ± 5 mmHg of a predefined target MAP) to achieve optimal CPP. Fluid administration was standardized in the two groups. The primary objective was the percentage of time patients were in target. Secondary outcomes included time spent over and under target. Over the four-hour study period, the mean percentage of time with MAP in target was greater in the CLV group than in the control group (95.8 ± 2.2% vs. 42.5 ± 27.0%, p < 0.001). Severe undershooting, defined as MAP < 10 mmHg of target value was lower in the CLV group (0.2 ± 0.3% vs. 7.4 ± 14.2%, p < 0.001) as was severe overshooting defined as MAP > 10 mmHg of target (0.0 ± 0.0% vs. 22.0 ± 29.0%, p < 0.001). The CLV system can maintain MAP in target better than nurses caring for severe brain injury patients.

Low Mean Perfusion Pressure Indexed to Body Surface Area is a Powerful Predictor of Poor Outcomes After Heart Transplantation in Patients With High Pre-Transplant Venous Pressure: A Clinical Study With Physiological Insights From Mathematical Modelling of Biventricular Heart Failure.

BACKGROUND & AIM: The deleterious consequences of chronically elevated venous pressure in patients with profound right ventricular or biventricular dysfunction are well known, including renal and hepatic dysfunction, and volume overload. The only option for these patients, if they fail optimal medical treatment, is a heart transplant, as they are not candidates for left ventricular assist device therapy. Mean perfusion pressure (MPP) is important in the outcomes of critically ill patients with high venous pressure. The question arises whether MPP is important for the outcomes of heart transplants in patients with elevated pre-transplant venous pressure. Medical management of heart failure patients with reduced ejection fraction involves lowering the systemic afterload with vasodilators while awaiting a transplant. We hypothesised that when venous pressure is elevated prior to transplant, a substantial reduction in systemic arterial elastance (Ea) through vasodilation may significantly decrease MPP, resulting in compromised end-organ function and consequent unfavourable outcomes after heart transplantation. This study aims to investigate whether a low MPP serves as a risk factor for adverse outcomes in heart transplant recipients with high venous pressure. METHOD: A retrospective analysis was conducted on 250 heart transplant recipients undergoing isolated heart transplantation at a single institution from October 2012 to March 2020. Right atrial pressure (RAP) of more than 15 mmHg was considered high. Additionally, Ea calculated as the ratio of end-systolic pressure to stroke volume, and MPP calculated as the difference between mean arterial pressure and RAP were considered in our analysis. The outcomes of transplantation were measured in terms of 90-day mortality and survival up to 7 years. RESULTS: High RAP was a significant risk factor for short-term and medium-term survival if Ea was low (<2.7 mmHg/mL, the median value). This group had 39.39% in-hospital mortality compared to 14.49% for RAP<15 mmHg (p∼0.005). When Ea was high, this difference in survival was not evident: 8% for RAP<15 mmHg vs 4.8% for RAP>15 mmHg (p∼0.550). This effect was mediated through a lower MPP, and the mortality due to lower MPP increased strikingly with higher body surface area (BSA). A negative correlation was observed between MPP indexed to BSA (MPPI) and the Model for End-Stage Liver Disease score (r∼-0.3580, p<0.0001) as well as creatinine (r∼-0.3551, p<0.0001). MPPI less than 40 mmHg/m2 was associated with poorer short-term (23.2% for MPPI<40 mmHg/m2 vs 7.1% for MPPI>40 mmHg/m2, p∼0.001) and medium-term survival. The impact of high RAP and low Ea on survival was evident even on medium-term follow-up; only 30% survival at 7 years follow-up for high RAP and low Ea vs 75% for RAP<15 mmHg (p∼0.0033). CONCLUSION: The acceptable blood pressure during vasodilator therapy in patients with high RAP needs to be higher, especially in those with higher BSA. MPPI less than 40 mmHg/m2 is a risk factor for survival, in the short and medium-term, after heart transplantation.

Contribution of intracranial pressure to human dynamic cerebral autoregulation after acute brain injury.

Cerebral perfusion pressure (CPP) is normally expressed by the difference between mean arterial blood pressure (MAP) and intracranial pressure (ICP) but comparison of the separate contributions of MAP and ICP to human cerebral blood flow autoregulation has not been reported. In patients with acute brain injury (ABI), internal jugular vein compression (IJVC) was performed for 60 s. Dynamic cerebral autoregulation (dCA) was assessed in recordings of middle cerebral artery blood velocity (MCAv, transcranial Doppler), and invasive measurements of MAP and ICP. Patients were separated according to injury severity as having whole/undamaged skull, large fractures, or craniotomies, or following decompressive craniectomy. Glasgow coma score was not different for the three groups. IJVC induced changes in MCAv, MAP, ICP, and CPP in all three groups. The MCAv response to step changes in MAP and ICP expressed the dCA response to these two inputs and was quantified with the autoregulation index (ARI). In 85 patients, ARI was lower for the ICP input as compared with the MAP input (2.25 ± 2.46 vs. 3.39 ± 2.28; P < 0.0001), and particularly depressed in the decompressive craniectomy (DC) group (n = 24, 0.35 ± 0.62 vs. 2.21 ± 1.96; P < 0.0005). In patients with ABI, the dCA response to changes in ICP is less efficient than corresponding responses to MAP changes. These results should be taken into consideration in studies aimed to optimize dCA by manipulation of CPP in neurocritical patients.