Certain routine medication could result in post-induction hypotension (PIH), such as angiotensin axis blockades, which are frequently administered as a first-line therapy against hypertension. Remimazolam is reportedly associated with lesser intraoperative hypotension than propofol. This study compared the overall incidence of PIH following remimazolam or propofol administration in patients managed by angiotensin axis blockades.This single-blind, parallel-group, randomized control trial was conducted in a tertiary university hospital in South Korea. Patients undergoing surgery with general anesthesia were considered for enrollment if the inclusion criteria were met: administration of an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, 19 to 65 years old, American Society of Anesthesiologists physical status classification ≤ III, and no involvement in other clinical trials.The primary outcome was the overall incidence of PIH, defined as a mean blood pressure (MBP) < 65 mmHg or decrease by ≥ 30% of the baseline MBP. The time points of measurement were baseline, just before the initial intubation attempt, and 1, 5, 10, and 15 min following intubation. The heart rate, systolic and diastolic blood pressures, and bispectral index were also recorded.Groups P and R included patients administered propofol and remimazolam, respectively, as an induction agent.P = 0.04, adjusted odds ratio = 0.32 [95% confidence interval 0.10–0.99]). The decrease in the MBP from baseline was 9.6 mmHg lesser in group R than in group P before the initial intubation attempt . A similar trend was observed for systolic and diastolic blood pressures. No severe adverse events were observed in either group.A total of 81 patients were analyzed, of the 82 randomized patients. PIH was less frequent in group R than group P , Republic of Korea (KCT0007488). Registration date: 30/06/2022. General anesthesia induction is frequently followed by hypotension, namely post-induction hypotension (PIH), which is reportedly 18–50% . The risPropofol is the most commonly administered agent for the induction of general anesthesia , 9. HoweAngiotensin axis blockades are widely administered in the surgical population, owing to their use as first-line treatment for hypertension. Adoption of an appropriate hypnotic agent is warranted to minimize hypotension and prevent potential complications in these patients. Therefore, we conducted a randomized controlled trial to compare the incidence of post-induction hypotension induced by remimazolam versus propofol in patients routinely administered angiotensin axis blockades.This study was designed as a single-blind, parallel-group, randomized controlled trial. The study was reviewed and approved by the Institutional Review Board of Wonju Severance Christian Hospital  and registered with the Clinical Research Information Service of Korea . This study was conducted in a tertiary university hospital in Wonju, Republic of Korea. This study was reported in compliance with the Consolidated Standards of Reporting Trials guidelines .The primary outcome was the incidence of hypotension following anesthesia induction. Hypotension was defined as a mean blood pressure (MBP) reduced 30% or more from the baseline MBP value or MBP < 65 mmHg, the threshold at which vital organ dysfunction can be initiated .Blood pressure was recorded six times during anesthesia. Time points T0, T1, T2, T3, T4 and T5, were baseline, immediately before the first attempt of intubation, a minute after intubation, 5 min after intubation, 10 min after intubation, and 15 min after intubation, respectively. In case of the arterial cannulation is present, real-time arterial blood pressure values were recorded. Otherwise, blood pressure was monitored using the oscillatory method through a pneumatic cuff at the area of the brachial artery. The MBP measured using this method is widely validated and considered reliable when measured under proper conditions .The secondary outcomes were heart rate, mean, systolic, and diastolic blood pressure , and bispectral index (BIS). These variables were measured from T0 to T5. An attending anesthesiologist assessed and recorded the primary outcomes and intraoperative variables. These data were verified by the corresponding author upon a reviewing the anesthesia records.Patients undergoing surgery with general anesthesia were considered for enrollment if the inclusion criteria were met: routine administration of ACEI or ARB, 19 to 65 years old, American Society of Anesthesiologists physical status classification of III or lower, and no involvement in other prospective clinical trials. The exclusion criteria were as follows: emergency and outpatient surgery, a candidate for transfer to an intensive care unit, body mass index ≥ 35, uncontrolled hypertension  , pregnanThe incidence of hypotension was considered as 84% in the patients receiving angiotensin axis blockades and propofol as an induction agent based on a previous study . An absoAssessment of eligibility and enrollment in the study was performed by the corresponding author. The participants were informed about the study via an informed consent form the day before the surgery, and provided sufficient time to determine their participation and sign the form. The participants were randomly assigned (1:1) to the propofol or remimazolam groups, namely groups P and R, respectively, using a sealed envelope system. A random allocation sequence was generated in advance by one of the authors (SWS) using R software. Paper cards containing the group allocations were sealed in opaque envelopes. Each sealed envelope was opened by another author (SK), and the patient notified the group allocation to an attending anesthesiologist 30 min before surgery. No anesthetic premedication was administered to the participants. The routine administration of ACEI or ARB was continued on the day of surgery.The induction drug was drawn in the anesthesia preparation room and the syringe was placed in a metal tin box. The patient and surgeon were blinded to the bolus drug administered by placing an opaque plastic cardboard, and blinding was maintained until the discharge of the patient from the post-anesthetic care unit.−1*min−1. The patient was preoxygenated for two minutes. In group P, propofol 2 mg per kg ideal body weight (IBW) mixed with lidocaine 20 mg was injected following preoxygenation. Remimazolam was infused at the rate of 0.1 mg/h for blinding. In group R, normal saline 0.2 mL per kg IBW was administered and remimazolam was infused at a rate of 6 mg*kg−1*h−1 initially.The baseline blood pressure, heart rate, pulse oximetry, and BIS  were recorded following the patient identification process. Other standard anesthetic monitoring devices, such as electrocardiograms, were also applied. Remifentanil infusion was initiated at a rate of 0.25 µg*kg−1*h−1 in both groups. The infusion rate of remimazolam was increased in increments of 0.1 mg*kg−1*hr−1, up to the 2 mg*kg−1*hr−1 for BIS higher than 60. Rocuronium 0.8 mg/kg IBW was administered for neuromuscular block, and orotracheal intubation was attempted two and half minutes later. The BIS was maintained in the range of 40–60. Ephedrine 6 mg or phenylephrine 50 µg was administered if MBP reduced 30% or more from the baseline MBP value or MBP < 65 mmHg.After loss of consciousness, remimazolam was infused at a rate of 1 mg*kgAn additional bolus of rocuronium 0.15 mg/kg IBW was administered in cases of decreased pulmonary compliance or discretion of the surgeon. Fentanyl 1 µg/kg and ramosetron 0.3 mg were administered for postoperative pain control and postoperative nausea and vomiting prophylaxis.IBM SPSS 26 Statistics for Windows  was used for statistical analysis, and R Statistics 4.2.2  was used for visualization. The chi-square test was performed to analyze the primary outcome. The unadjusted and adjusted odds ratio of remimazolam versus propofol for the incidence of hypotension was calculated by logistic regression analysis, and the covariates were the administration of the drugs causing angiotensin axis blockade on the day of surgery and type of surgery.P < 0.05.Decrease in the MBP, SBP, and DBP  at T1 to T5 were compared using the t-test with Bonferroni correction to correct the multiplicity of the comparisons. The BIS and heart rate at T0 to T5 were compared using the t-test with Bonferroni correction. Other continuous variables were compared using the t-test, and categorical variables were compared using the chi-square test. Statistical significance was set as Blood pressure > 300 mmHg or < 30 mmHg and heart rate > 200 beats per minute were excluded from the analysis. Missing value analysis by SPSS revealed a few missing values (< 5%) in the total remifentanil dose and BIS values; however, they were randomly distributed. The missing values were excluded from the analysis.From August 2021 to August 2022, 124 patients were assessed for eligibility and 82 patients were enrolled . The absolute difference of hypotension was 20.4%, and the unadjusted odds ratio of incidence of hypotension was 0.34 . The adjusted odds ratio according to the type of surgery and administration of angiotensin axis blockade was 0.32 (95% CI 0.10–0.99). Specifically, MBP, SBP, and DBP decreased more abruptly in group P than in group R immediately before the intubation attempt . No other adverse events were observed.A remarkable proportion of patients (> 70%) in this study developed hypotension. This is higher than the general population and supports the finding that the patients routinely administered angiotensin axis blockades are vulnerable to PIH , 14. PIHIn cases of intraoperative hypotension, the amount of reduction in the blood pressure is also critical , 19. A gAnother benefit of remimazolam as an induction agent is that the drug has the antagonist. There are some cases where rapid recovery after loss of consciousness is required. One example is difficult airway management. According to the multiple airway management guidelines, emergence and recovery of spontaneous ventilation are warranted in cases of supraglottic airway or endotracheal tube placement fails, but oxygenation is still possible –23. The A trend of higher BIS was observed in participants administered remimazolam than in those who were administered propofol. Previous studies have reported a discrepancy between the BIS and sedative state in patients administered remimazolam , 25. ThiOur study has certain limitations. First, due to the loading dose of remimazolam in group R, the effect-site concentration after the loss of consciousness could be higher in group R. Further study adopting a target-controlled infusion model is required to overcome this limitation. Second, generalizability is limited due to the exclusion of high-risk surgical populations who require preparation for intensive care units. In addition, long-term postoperative outcomes, such as 30-day mortality, have not been studied. Further well-designed studies addressing the long-term postoperative impact of intraoperative hypotension in patients administered ARB or ACEI are warranted.Patients routinely administered angiotensin axis blockades are vulnerable to hypotension. Remimazolam results in lesser blood pressure reduction and lower instances of frequent PIH than propofol.


In previous studies, sun-protective behaviors increased cardiovascular incidence. Our present article is to further analyze the potential relationship between sun-protective behaviors  and hypertension.The present cross-sectional study evaluated 8,613 participants (aged 20–60 years) from the National Health and Nutrition Examination Survey (NHANES) obtained between 2009 and 2014. We performed multiple logistic regression analysis to examine the relationship between sun-protective behaviors and hypertension. Subgroup analysis was then performed. Multiple linear regression analysis was utilized to examine the relationship of sun-protective behaviors and each sun-protective behavior with systolic and diastolic blood pressure, stratified by sex and race.n = 127,909,475) were applied in our study, including 1,694 hypertensive subjects. Our study demonstrated that sun-protective behaviors of the 2–3 category were associated with increased risk of hypertension, but not with higher systolic and diastolic blood pressure. In subgroup analysis, men, Mexican American, and 25 < BMI ≤ 30 who reported sun-protective behaviors (2–3) were prone to hypertension. Multiple linear regression models showed that non-Hispanic white men with sun-protective behaviors (2–3) were positively associated with systolic and diastolic blood pressure. The association between other-Hispanic men with frequent wearing long-sleeved clothing and diastolic blood pressure was positively correlated.A total of 8,613 participants  were positively associated with systolic and diastolic blood pressure. These findings suggested that excessive sun-protective behaviors should be avoided.The online version contains supplementary material available at 10.1186/s12889-023-16439-4. Hypertension, defined as measured systolic pressure of ≥ 140 mmHg and diastolic pressure of ≥ 90 mmHg, is a major health problem that traditionally gives rise to atherosclerotic cardiovascular diseases (CVDs) . The preMany studies have found that sunlight provides significant benefits . SunlighTherefore, the present study investigated a potential connection between sun-protective behaviors and hypertension by analyzing adult (aged 20–60 years) patient data from the National Health and Nutrition Examination Survey (NHANES) from 2009–2014.http://www.cdc.gov/Nhanes. A total of 8,613 individuals were included in the study after excluding patients with missing information on sun-protective behaviors, hypertension, and other covariates. The flow chart of the systematic selection process is illustrated in Fig. Statistical data from the NHANES were analyzed to investigate the relationship between sun-protective behaviors and hypertension. The NHANES is major research study that was carried out by the National Center for Health Statistics, the Centers for Disease Control and Prevention, to assess the state of health and nutrition in the U.S. population. The present study received approval from The National Center for Health Statistics and written informed consent was obtained from all participants. More information is available in the NHANES database, Blood pressure measurements were obtained by professionally trained personnel. Participants with hypertension were informed by their physicians that they conformed to the hypertension criteria. The criteria are systolic blood pressure ≥ 140 mmHg and diastolic blood pressure ≥ 90 mmHg in three blood pressure measurements taken at the same time on a non-same day.Sun-protective behavior was assessed using three variables that included staying in the shade, wearing long-sleeved clothing, and applying sunscreen. These variables were recorded as “always”, “most of the time”, “sometimes”, “rarely”, and “never” in the NHANES. The present analysis categorized the three variables as “rare” (never or rarely), “moderate” (sometimes), or “frequent” . Sun-protective behaviors were then classified as 0, 1, and 2–3 based on the number of behaviors with frequent use in three variables .2) ratio. PIR has been used in several studies as a marker of economic status  level  , 17, milc status . Smokingc status . Drinkin–60 yearsc status .http://www.R-project.org) was used to analyze the dataset. Categorical variables were expressed as percentages (%) and compared using χ2. Continuous variables were expressed as means ± standard deviation (SD) and compared using dependent-sample t-tests  or Kruskal–Wallis rank sum tests .R (P < 0.05.With sun-protective behaviors (0) as the reference category, multiple logistic regression models were utilized to evaluate the relationship between sun-protective behaviors and hypertension. Subgroup analyses were stratified by sex, race, and BMI. Three models were used in the present analysis: Model 1 (an unadjusted model), Model 2 , and Model 3 . When stratified by a certain variable, the model does not adjust this variable. We used multiple linear regression models to analyze the relationship of sun-protective behaviors and each sun-protective behavior with systolic and diastolic blood pressure, stratified by sex and race. Statistical significance was recognized by the value of n = 127,909,475), including 4,199 men and 4,414 women. The number of sun-protective behaviors with hypertensive participants was 1,964. The overall means (± SD) of systolic and diastolic blood pressure were 118.53 ± 14.36 and 71.60 ± 11.07. The mean age of study population was 39.01 ± 11.58 years. The percentages of sun-protective behaviors with 0, 1, and 2–3 were 47.7%, 36.8%, and 15.5%. The mean (± SD) of BMI was 28.97 ± 6.87 kg/m2. Race included Mexican American , other Hispanic , non-Hispanic white , non-Hispanic black , other race . The demographic data characteristics organized by sun-protective behaviors status are represented in Table The study analysis included data for 8,613 eligible participants (weighted P = 0.0496) compared to those without sun-protective behaviors in Model 3. In the subgroup analysis of the fully-adjusted model .Odds ratio (OR) was used as a measure of risk. Multiple logistic regression analysis was used to determine the association between sun-protective behaviors and hypertension Table . Particiel Table , we founP = 0.0052; 95% CI = 0.08–5.08, P = 0.0433).We also assessed the association of sun-protective behaviors with systolic and diastolic blood pressure using multiple linear regression analysis Table . We founP = 0.0253).Additional multiple linear regression analysis was used to assess the association of each sun-protective behavior with systolic and diastolic blood pressure  radiation was associated with lower blood pressure . FeeliscSun-protective behaviors are different for sexes. Pinault et al. found that sun-protective behaviors in females are more significant in the summer months for Canadian adults . And difTo acknowledge the relationship of sun-protective behaviors with systolic and diastolic blood pressure stratified by sex and race, we performed a multiple linear regression and found no significant differences. Because systolic and diastolic blood pressure data were collected after antihypertensive medication or life interventions, which may have contributed to the fact that sun-protective behaviors were not associated with systolic and diastolic blood pressure. And it was difficult to obtain pre-intervention systolic and diastolic blood pressure due to the limited database. However, even with post-intervention data, we found significant differences between non-Hispanic white men who reported sun-protective behaviors (2–3) with diastolic and systolic blood pressure, suggesting that sun protection programs should be more important for this population.In our study, analysis of each sun-protective behavior and hypertension combination is shown in Additional file 1. After adjusting for confounders, the outcomes showed that the association between other race men who reported wearing long-sleeved clothing frequently and diastolic blood pressure was positively correlated. Staying in the shade and applying sunscreen were not associated with increased risk of hypertension. There are no relevant studies examining the relationship between each sun-protective behavior and hypertension, and more study is needed to verify the results.Hypertension causes a great number of CVD morbidity and mortality cases . DecreasThere were several limitations in the present study. Firstly, the cross-sectional nature of the study introduced intrinsic limitations. The data from the NHANES were obtained between 2009 and 2014. In the future, a randomized controlled study will be necessary to verify these results. Secondly, the history of hypertension and sun-protective behaviors were self-reported, resulting in under- or over-reported questionnaire outcomes. Thirdly, due to the limited database, the systolic and diastolic blood pressure data were obtained post-intervention. This may lead to differences in results. Finally, the participants were 20–60-years-old. Given that hypertension often occurs in the elderly, future research will need to focus on patients older than 60 years.The present cross-sectional study results demonstrated that sun-protective behaviors of the 2–3 category were associated with increased risk of hypertension, but not with higher systolic and diastolic blood pressure. We only found that non-Hispanic white men who reported sun-protective behaviors (2–3) were positively associated with systolic and diastolic pressure. Consequently, patients should be encouraged to avoid excessive sun protection due to the high risk of hypertension and sun-protective behaviors should be sensible for non-Hispanic white men. Future clinical studies could focus on developing specific sun protection programs for different populations.Additional file 1. Association between each sun-protective behavior with SBP and DBP.


Since its introduction in the 1960s, intracranial pressure (ICP) monitoring has become an indispensable tool in neurocritical care practice and a key component of the management of moderate/severe traumatic brain injury (TBI). The primary utility of ICP monitoring is to guide therapeutic interventions aimed at maintaining physiological ICP and preventing intracranial hypertension. The rationale for such ICP maintenance is to prevent secondary brain injury arising from brain herniation and inadequate cerebral blood flow. There exists a large body of evidence indicating that elevated ICP is associated with mortality and that aggressive ICP control protocols improve outcomes in severe TBI patients. Therefore, current management guidelines recommend a cerebral perfusion pressure (CPP) target range of 60–70 mm Hg and an ICP threshold of >20 or >22 mm Hg, beyond which therapeutic intervention should be initiated. Though our ability to achieve these thresholds has drastically improved over the past decades, there has been little to no change in the mortality and morbidity associated with moderate-severe TBI. This is a result of the “one treatment fits all” dogma of current guideline-based care that fails to take individual phenotype into account. The way forward in moderate-severe TBI care is through the development of continuously derived individualized ICP thresholds. This narrative review covers the topic of ICP monitoring in TBI care, including historical context/achievements, current monitoring technologies and indications, treatment methods, associations with patient outcome and multi-modal cerebral physiology, present controversies surrounding treatment thresholds, and future perspectives on personalized approaches to ICP-directed therapy. However, because of the notable risks of ICP-lowering therapeutics, clinicians must balance the danger of elevated ICP with the iatrogenic risks of such therapies. Therefore, accurate ICP monitoring, that is safe and simple to use, is necessary to guide ICP maintenance.Since its inception, intracranial pressure (ICP) monitoring has established itself as a fundamental pillar of neurocritical care practice. Persistently elevated ICP can have disastrous effects on the cerebral environment, secondary to brain herniation or insufficient cerebral blood flow (CBF). The latter can be illustrated by the inherent relationship that exists between ICP, cerebral perfusion pressure (CPP), and mean arterial pressure (MAP); CPP = MAP – ICP. It has been shown that such elevations in ICP are associated with poorer outcomes,14 Despite major improvements in our ability to achieve such thresholds over the past few decades, there has been very little change in the morbidity and mortality associated with severe TBI.15–17 This is, in part, attributable to a failure to consider individual phenotype, given that cerebral physiological response to TBI varies greatly between persons.18–23 A potential solution to this problem is through the development of individualized ICP thresholds that are patient specific and continuously derived.Current management guidelines now include ICP thresholds, >20 or >22 mm Hg, beyond which therapeutic intervention is recommended.In this narrative review, we will begin by providing a quick historical overview of the development of ICP monitoring. We will then discuss ICP monitoring technologies, indications for their use, and therapeutic approaches for controlling ICP. We will also examine treatment thresholds and their associations with outcome and multi-modal cerebral physiology. Finally, we will conclude with a discussion of the controversies surrounding the use of these thresholds and future directions in ICP-directed care.24–27 In 1824, a former student of Monro, George Kellie, provided support for this hypothesis by demonstrating that intracranial blood volume was relatively similar between autopsies, regardless of the cause of death.28 Based on this observation, Kellie asserted that in order for total intracranial blood volume to remain constant, decreases in arterial blood volume must be compensated for by engorgement of the venous system.28 The work of these two Scotsmen would set the framework for what would later become known as the Monro-Kellie doctrine. A few years later, another Scottish surgeon, John Abercrombie, further supported this growing hypothesis by demonstrating that, as long as the skull and dura remain intact, the brain does not exsanguinate like other organs post-mortem.29 This indicated that the cranium was a closed system with a relatively negative internal pressure.The concept of ICP—the pressure created by the contents of the cranium—was first introduced in 1783 when Alexander Monro described the cranium as a rigid compartment containing a “nearly incompressible” brain, and concluded that intracranial blood volume must therefore remain constant.30–32 However, the so-called Monro-Kellie doctrine, as it is known today, was not fully synthesized until the renowned American neurosurgeon, Harvey Cushing, compiled the various contributions into a succinct synopsis, which, to this day, serves as a fundamental concept in the field of neurosurgery.34Up until this point, the developing doctrine only considered the presence of blood and brain tissue; however, this changed when the French physiologist, François Magendie, described cerebrospinal fluid (CSF) circulation, and the English physician, George Burrows, incorporated its role into the hypothesis.33 This doctrine lays out the fundamental principles that dictate ICP dynamics and is crucial for understanding the detrimental effects of ICH.34 It should be noted that this concept does not apply to the infant given that the sutures of the infantile skull have not yet fused and thus allow for some degree of volumetric compliance.35The modern doctrine states that, with an intact skull and dura, the cranial compartment is of fixed volume and that the combined intracranial volume of brain parenchyma, blood, and CSF must remain constant, and therefore an increase in the volume of one component must be offset by a decrease in the volume of another component.34 This compensatory reserve is primarily provided by the brain's venous blood pool, which can be adjusted to maintain stable ICP.34 The brain's CSF pool can also contribute to the maintenance of physiological ICP, however, to a lesser extent.34 When a pathological increase in intracranial volume occurs, the initial increase is readily compensated for by the movement of venous blood and CSF out of the cranium; however, this mechanism is limited and can quickly become depleted.24 Once this point of decompensation is reached, even a miniscule elevation in volume can result in substantial increases in ICP.27 The resulting ICH can have devastating effects on the intracranial environment, such as cerebral ischemia and brain herniation, both of which can cause irreversible brain damage.34 Such exhaustion of the compensatory reserve occurs in a wide range of pathological states, such as TBI and intracranial space occupying lesions or bleeds.24 Therefore, maintaining physiological ICP, generally defined as ∼5–15 mm Hg in the healthy supine adult,25 is critical for limiting further brain injury in such patients, with accurate monitoring of ICP necessary to guide clinical management and prognostication.34Given that the contents of the cranium are relatively incompressible, stable ICP requires a volumetric equilibrium, where changes in the volume of one component are compensated for by changes in the volume of the other two components.36 However, it was not until the early 1950s when the first true ICP measurement was taken. It was two Frenchmen, Jean Guillaume and Pierre Janny, who used an external ventricular drain (EVD), which involves placing a catheter into the anterior horn of a lateral ventricle to allow CSF to flow externally, and a U-tube manometer to measure ICP.36–39 This laid the framework for the development and implementation of modern ICP monitoring. A decade later, the Swedish neurosurgeon, Nils Lundberg, developed an improved monitoring technique that facilitated the continuous measurement of ICP.36 His technique utilized a strain-gauge pressure transducer and a paper recorder, which allowed for temporal observations of ICP and characterization of its waveform.40 He continued on to establish protocol for its use and demonstrate its efficacy and safety; however, despite this, there was widespread skepticism surrounding its utility and safety among the neurointensive care community.36In 1916, the German neurologist, Hans Queckenstedt, made the first attempts at measuring intraspinal pressure when he performed lumber punctures and approximated pressure using U-tube manometry.36 At the turn of the century, ICP monitoring was finally incorporated into standard neurocritical care practice when its use was included in the U.S. Brain Trauma Foundation (BTF) guidelines.41 Today, ICP monitoring is considered a cornerstone of neurocritical care as an indispensable tool for guiding the therapeutic management of TBI.38For the most part, ICP monitoring remained primarily a research tool until the late 1970s and 1980s, when its use finally began gaining acceptance because of growing evidence, indicating that aggressive ICP maintenance resulted in improved outcomes.34 This method involves inserting a catheter directly into a ventricle, usually through a coronal burr hole.25 Currently, the catheter is connected to an external strain-gauge pressure transducer, whose electrical resistance varies depending on the extent it is deformed by the pressure of the surrounding environment.42 The electrical resistance then dictates the voltage of the device's internal circuitry, thus producing pressure measurements.42 A major advantage of this setup is that it allows for recalibration of the device at any time by resetting the device to atmospheric pressure.25 The EVD is also highly reliable and allows for intrathecal administration of drugs and therapeutic drainage of CSF.25 However, this device's practicality is hindered by its highly invasive nature and its association with infectious and hemorrhagic complications, 5–20%44 and 2–10%,46 respectively.34 Additionally, EVD placement may be difficult in cases involving small or compressed ventricles.25Since the introduction of ICP monitoring using the EVD, various other methods for monitoring ICP have been developed and popularized. However, intraventricular pressure monitoring through the use of an EVD remains the gold standard of ICP monitoring.25A newer invasive method for monitoring ICP is the use of implantable microtransducers, which include fiber optic devices, strain gauge devices, and pneumatic sensors.34 A diaphragm and a microprocessor amplifier are then used to detect changes in the intensity of the reflected light to produce an ICP measurement and its waveform.24 Though the associated risk of infection or hemorrhage is nearly negligible, this method is relatively expensive, can be quite meticulous to set up, and commonly demonstrates a baseline drift.24In fiber optic devices, such as the Camino ICP Monitor, variations in ICP displace a mirror that alters the intensity of light which is reflected back to a fiber optic cable.34 These devices have been extensively studied and have been demonstrated to be highly accurate and negligibly associated with infectious and hemorrhagic complications.24 However, similar to fiber optic devices, baseline drift is a significant problem in these devices.24With strain gauge devices, such as the Codman MicroSensor, the Raumedic Neurovent-P ICP sensor, and the Pressio sensor, changes in ICP cause a diaphragm within the sensor to bend, resulting in changes in its electrical resistance and thus allowing for ICP measurement.34 These devices are becoming increasingly popular because of recent innovations that allow for CSF drainage and automated drift corrections.24Pneumatic sensors, such as the Spielberg ICP Monitor, use a small balloon at the tip of a probe, on which the pressure of the surrounding tissue is exerted, allowing them to produce ICP measurements.34 These devices provide a less invasive alternative to the EVD that are more simple to place, are associated with lower infection and hemorrhage risk, and have a lower incidence of waveform damping and signal artifacts, while at the same time maintaining a close correlation to the gold-standard measurements.24 However, most microtransducers suffer from the inability to recalibrate, and thus the problem of baseline drift, as well as increased cost.34Microtransducer devices are most often placed intraparenchymal, usually in the right frontal cortex; however, they can also be placed in the subarachnoid, subdural, or epidural spaces.25 The magnitude of baseline drift can be determined by looking at the ICP value that is measured when a device is removed versus when it was placed.25 The problem of baseline drift presents a clear concern for patient care, given that proper treatment requires accurate ICP measurements to guide management. The exact mechanism behind this phenomenon, in regard to ICP monitoring devices, remains unclear. For a thorough overview of the accuracy of various ICP monitoring devices and the extent of baseline drift in these devices, we refer the reader to an article by Pelah and colleagues.47As discussed above, a major shortcoming of most microtransducer devices is the problem of baseline drift, also known as zero drift. Baseline drift describes the phenomenon where a sensor reports increasingly inaccurate measurements over time, resulting from a lack of continuous calibration.24 Such non-invasive methods should, in theory, eliminate infectious and hemorrhagic complications, allow for safe screening of low-risk persons, be more simple and convenient to use, be readily available, and be relatively inexpensive.34 Dozens of promising non-invasive technologies exist, including transcranial Doppler, transocular ultrasonography measuring optic nerve sheath diameter, and near infrared spectroscopy.34 Despite the great strides that have been taken in the development of non-invasive ICP monitors, invasive devices remain to be the most accurate methods to measure ICP, with EVDs and intraparenchymal strain gauge devices being the most commonly used in clinical practice.24 The various invasive and non-invasive monitoring modalities are summarized in Though invasive methods of measuring ICP are accurate and reliable, their invasive nature and risk of complications have driven research studying potential non-invasive alternatives.13 However, the lack of a supporting randomized control trial prevented its establishment as a standard of care early on.1 Given the invasive nature of ICP monitoring and its associated risks, its use should be limited to patients who are at high risk of ICH. Multiple studies identified comatose patients, those with a Glasgow Coma Scale (GCS) score of ≤8, as a high-risk population.11 Additionally, Narayan and colleagues found that, within this population, those with an abnormal computerized tomography (CT) scan had a significantly higher incidence of ICH than those with a normal scan, ∼60% and 13%, respectively.11 Other studies demonstrated similar findings.48 However, patients with normal CT scans tended to demonstrate similar incidence rates as those with abnormal scans when they presented with at least two of the following adverse features: age >40 years, motor posturing, and systolic blood pressure <90 mm Hg.11 Given that symptoms of elevated ICP, such as headache, are not usually identifiable in a comatose patient, and clinical signs, such as papilledema, do not consistently present with ICH, ICP monitoring is necessary in such high-risk populations.49The BTF guidelines recommend the use of ICP monitoring for certain severe TBI-injured patients.13 However, it should be noted that most of these findings are from studies that were done over four decades ago and that CT technology has significantly improved since then. Monitoring in patients with mild or moderate TBI is not routinely recommended, because of its invasive nature and the relatively low risk of ICH in this population.13 However, clinicians may consider monitoring in this population in certain scenarios, such as when treatment that prevents proper serial neurological examinations or can cause elevations in ICP is required.49 ICP monitoring is usually continued until ICP remains normal for a prolonged period of time, usually 24–48 h, without ICP-lowering therapy.49 Unfortunately, despite the recommendations of the BTF, up to half of patients who are indicated for ICP monitoring do not receive it.51Based on these findings, the BTF guidelines recommend initiation of ICP monitoring in patients with severe TBI, defined as a GCS of 3–8, with an abnormal CT scan or at least two of the adverse features detailed above.52 It should be noted that this is considered a relative contraindication that clinicians may choose to disregard in certain situations based on clinical judgement. In the coagulopathic patient, the placement of an ICP monitor or EVD is preferably avoided until the coagulopathy can be reversed; however, in emergent cases, placement can be performed in tandem with correction. Placement of an ICP monitor is rarely considered an emergent procedure and will usually be deferred until after reversal. On the other hand, EVDs are occasionally used for aggressive ICP reduction, and can be placed regardless of the presence of a coagulopathy.The only contraindication for ICP monitoring is the presence of a coagulopathy.54 Additionally, monitoring the ICP waveform shape can assist in evaluating the effectiveness of interventions aimed at improving craniospinal compliance. For example, after initiating treatment for elevated ICP, such as administering osmotic agents, changes in the waveform shape can indicate the response to treatment and guide further management decisions.As discussed earlier, a key protection mechanism is the ability of the craniospinal system to compensate for volumetric changes. Exhaustion of this craniospinal compliance can rapidly result in injury to the brain and is therefore important to monitor. Though ICP level itself can give some insight into the state of this compliance, it usually is unable to identify impaired compliance in time to prevent its detrimental effects. The shape of the ICP waveform can give further insight into the state of craniospinal compliance and help detect pathologies earlier. 24 However, the prominent saw-tooth pattern pulsations are primarily driven by the cardiac cycle. The shape of the ICP waveform is influenced by several factors, including the compliance of brain tissue, CSF production, absorption, and circulation dynamics.The ICP waveform represents the dynamic changes in ICP. When measured continuously, ICP demonstrates a pulsatile waveform made up of a waveform corresponding to the respiratory cycle superimposed onto a waveform corresponding to the cardiac cycle.55 This ICP level at which AMP begins to decrease instead of increase is known as the upper breakpoint of amplitude-pressure characteristic.55 Increased AMP is often considered a sign of poor craniospinal compliance given that it indicates that there are larger changes in pressure in response to changes in volume (blood flow). Further, it has been shown that elevated AMP is associated with poorer outcome in TBI.56The aspect of the ICP waveform that has been most looked at is the fundamental amplitude of the pulse waveform (AMP). Usually, increases in ICP are associated with increases in AMP; however, at very high levels of ICP, AMP begins to decrease. This is because when ICP becomes very high, the pressure on the vasculature exceeds diastolic ABP, causing cerebrovascular collapse and cessation of diastolic flow.57 This index is a measure of compensatory reserve and can be used to estimate craniospinal compliance. A RAP value near 0 indicates that variation in AMP is not driven by changes in ICP, thus suggesting intact craniospinal compliance, whereas values near 1 indicate that AMP changes are being driven by ICP changes and that there is a lack of compliance. Additional waveform analysis techniques exist, such as the analysis of waveform patterns or measurement of the slope of pulsations; however, a full overview of these techniques is not included here.Another important measure that can be derived from waveform analysis is the Pearson correlation between AMP and ICP, termed the RAP index.49 However, it should be noted that baseline ICP levels can vary greatly between persons. For example, a 2012 study by Berdahl and colleagues found a direct linear relationship between body mass index (BMI) and mean CSF pressure , with mean pressure increasing from 8.6 ± 2.1 mm Hg for a BMI of 18.0–14.1 ± 2.5 mm Hg for a BMI of 39.58 They also noted that this elevation in mean CSF pressure was not necessarily associated with poorer outcome, thus indicating that physiological ICP may be higher in patients who are obese.58 Therefore, such patient-specific factors should be considered when determining baseline levels and deciding whether initiation of ICP-lowering therapeutics is warranted.The primary utility of ICP monitoring is to guide therapeutic management aimed at maintaining physiological ICP and preventing ICH. In the supine adult, normal ICP is loosely defined as ICP of 5–15 mm Hg, with mild ICH generally described as 20–30 mm Hg and severe ICH characterized as sustained ICP above >40 mm Hg.24 CPP, ICP, and MAP are inherently related through the following formula: CPP = MAP – ICP.24 MAP is defined as the average arterial blood pressure (ABP) over one cardiac cycle and is typically acquired by indwelling arterial lines for continuous blood pressure acquisition, with zeroing, for the purposes of ICP/CPP-directed management, suggested at the level of the tragus by recent expert consensus statements.60 Normally, consistent CBF can be maintained over a range of CPP values attributable to the brain's inherent autoregulatory mechanism.61–63 However, this mechanism is limited and is often impaired in TBI-injured patients, exposing the brain to pressure-passive insults.64 Therefore, preventing ICH is essential for not only preventing herniation of brain tissue, but also maintaining sufficient CPP to adequately perfuse cerebral tissue and prevent ischemia.The goal of maintaining physiological levels of ICP is to prevent secondary brain insults caused by brain herniation and insufficient CBF.49 It should be noted that, though ICP should remain relatively stable over time in the normal state, it does not remain perfectly constant. As mentioned earlier, ICP demonstrates a pulsatile waveform made up of a waveform correlating with the respiratory cycle superimposed onto a waveform correlating with the cardiac cycle.24 Regular fluctuations in ICP are also expected during postural changes and with variations in adrenergic tone.35 Therefore, in the clinical setting, time-averaged ICP is usually used for establishing baseline values and only prolonged elevations in ICP are considered clinically significant.34 A patient example of raw cerebral physiological data and time-averaged recordings is presented in Management guidelines recommend initiation of ICP-lowering therapies when CPP drops below 60 mm Hg or ICP surpasses 20 or 22 mm Hg.49 When ICP is elevated for prolonged periods of time, additional therapeutic interventions are required to control ICP.General care for ICH involves preventing and treating factors that exuberate elevations in ICP, such as obstruction of venous return, respiratory failure, hypertension, hyponatremia, anemia, fever, and seizures.2) of blood, resulting in constriction of cerebral vessels and a reduction of cerebral blood volume, thus reducing ICP.49 However, hyperventilation is of limited utility because of the short-term nature of its effects, potential for rebound hyperemia, and risk of cerebral ischemia.49 In a randomized control study by Muizelaar and colleagues, it was demonstrated that prolonged hyperventilation leads to poorer outcomes in severe TBI-injured patients by precipitating ischemic episodes.65 Therefore, its use is largely restricted to the acute treatment of elevated ICP, allowing time for other ICP-lowering therapies to be initiated.49 Because hyperventilation accelerates CO2 elimination, end-tidal CO2 (EtCO2) is closely related to the extent of hyperventilation and is therefore used for titrating this therapy. A patient example of the association between ICP and EtCO2 can be found in A commonly used method for reducing ICP is hyperventilation. This therapeutic approach decreases the partial pressure of carbon dioxide , an indicator of the depth of sedation, to a bolus dose of a sedative can be found in Sedatives, analgesics, and paralytics are routinely used in neurocritical care practice to prevent agitation and elevations in blood pressure, both of which can cause increases in ICP.49 However, its use is limited in that overly aggressive drainage can result in ventricular collapse with loss of ICP transduction and that it fails to tackle the underlying pathophysiology present in TBI, which is rarely hydrocephalus. Therefore, although a popular therapeutic method historically, there has been a shift away from its use for managing trauma-related ICH. Currently, some clinicians still elect to use EVDs because of their ability to rapidly reduce and monitor ICP while more escalations in surgical or medical management are arranged; however, with the improvements in microtransducer ICP monitoring devices and the safety profiles of other therapeutic options, this pattern is likely to continue.CSF drainage, with the use of an EVD, is an effective method for quickly and dramatically reducing ICP.49 Recent clinical trials indicate that induced hypothermia results in lower ICP, but has no beneficial impact on clinical outcome.72 Steroids have been demonstrated to decrease ICP in brain tumor patients; however, for other pathologies, such as TBI, steroids have been shown to have detrimental effects and therefore should not be used.73 Emergent surgical procedures, such as mass resection and decompressive craniectomy, are utilized when ICH occurs rapidly or is unresponsive to medical therapeutics.49 It should be noted that all therapeutic options for reducing ICP demonstrate notable risks; therefore, the clinician must balance the threat of ICH with the iatrogenic risks of such therapies.1Additional ICP-lowering therapies exist, such as induced hypothermia, administration of steroids, and surgical intervention, which can be used in conjunction with the therapeutics described above.1–10 There was also evidence that ICP monitoring could contribute to more accurate outcome prognostication than the use of solely clinical exaination.10 Further, studies had demonstrated that ICP control increases the probability of recovery, by reducing the risk of brain herniation and cerebral ischemia.12 A 1977 study by Becker and colleagues reported a reduction in mortality rate when an intensive management protocol that utilized ICP monitoring was included into patient care.5 Similarly, a prospective placebo-controlled study by Eisenberg and colleagues also reported improved outcome when ICP was controlled.4 Ghajar and colleagues compared a group of patients who had their ICP monitored and were treated for elevated ICP versus a group who did not. They found that the mortality rate of the monitored group was significantly lower than the non-monitored group, 12% and 53%, respectively.74 It had also been shown that systemic hypotension was associated with poorer outcome, likely as a result of inadequate cerebral perfusion attributable to the direct relationship that exists between blood pressure and CPP.75 In a study by Marmarou and colleagues, it was shown that the proportions of time with ICP above 20 mm Hg and blood pressure below 80 mm Hg were highly predictive of outcome.2At the time of the development of the BTF guidelines, there existed an extensive body of literature that indicated that higher ICP was associated with poorer outcomes.77 Additionally, recent work has described a strong relationship between elevated ICP and mortality in severe TBI.78–84 The association between ICP and favorable outcome has also been validated; however, it has been found to be less robust than that of mortality.81 Interestingly, the only randomized control trial investigating ICP monitoring to date, by Chestnut and colleagues, found that management directed using ICP monitoring did not result in statistically superior outcomes when compared to management based solely on clinical examination and imaging.85 This study, which took place in Bolivia and Ecuador, essentially compared two methods of ICP-directed therapy, one where ICP was monitored directly and the other where ICP was estimated using clinical examination and imaging, and does not comment on the effect of ICP control itself. Therefore, these results do not refute the importance of ICP-based management strategies.Recent literature has affirmed many of the above-described findings, with a multitude of studies demonstrating that aggressive ICP maintenance is associated with improved outcome.20 A recent systematic review by our group found that there is very limited literature that demonstrates direct statistical associations between such modalities and ICP above/below guideline-defined thresholds.86Multi-modal monitoring refers to the various bedside physiological monitoring modalities that supplement ICP monitoring and provide the clinician with a more complete picture of the patient's cerebral physiological state. These modalities include those that monitor CBF, systemic hemodynamics, brain oxygenation, cerebral autoregulation, cerebral metabolism, and electrophysiology.87–91 For the category of systemic hemodynamics, a study by Zeiler and colleagues found that there was a statistically significant difference in MAP between a patient cohort with a mean ICP of <15 mm Hg and a cohort with a mean of >20, 82, and 89 mm Hg, respectively (p = 0.0009).92 A study by Mowery and colleagues demonstrated that increasing ranges of ICP were associated with increased cardiac decoupling, with analysis of variance testing producing a p value of <0.001.93 A study by Narotam and colleagues, looking at parenchymal brain oxygen tension (PbtO2), found that PbtO2 <20 mm Hg is associated with ICP >20 mm Hg, with chi-square analysis producing a chi-square value of 9.34 (p < 0.01).94We were not able to find any studies demonstrating an association between ICP above/below threshold and CBF directly; however, multiple studies were found for CBF velocity. These studies found that CBF velocity had little to no relationship with ICP above/below threshold within the therapeutic range of ICP.p values of <0.001, 0.003, and 0.003, respectively, on Mann-Whitney U testing.92 No studies that demonstrated an objective association between ICP above/below threshold and a metric of either electrophysiology or cerebral metabolism were found in the systematic review.86Surrogate metrics of cerebral autoregulation have also been shown to be associated with ICP above/below threshold. Zeiler and colleagues demonstrated that mean PRx, pulse amplitude index , and RAC (the correlation [R] between AMP [A] and CPP [C]) all significantly differed between a patient cohort with a mean ICP <15 mm Hg and a cohort with a mean > 20 mm Hg, producing 2 Through a logistic regression analysis, they found that the proportion of time with ICP >20 mm Hg correlated the best with outcome.2 This result is in keeping with other smaller studies that evaluated threshold values between 15 and 25 mm Hg.95–99 A study by Saul and Ducker compared outcomes between a group of patients who were treated in 1977–1978 using an ICP threshold of 20–25 mm Hg versus a group that was treated in 1979–1980 using a more strict protocol with a threshold of 15 mm Hg.96 They found that the mortality rate was significantly lower in the second group, 46% and 28% (p < 0.0005), respectively.96 This suggests a possible benefit in using a lower ICP threshold; however, differences in time period and treatment protocols between two groups clouds the certainty of any stand-alone effects of lowering the treatment threshold.95Though there was a significant amount of literature demonstrating the association between ICP and outcome before publication of the BTF guidelines, there remained questions revolving around what to use as a treatment threshold. In 1991, Marmarou and colleagues conducted a study on 428 severe TBI-injured patients, evaluating ICP thresholds, in 5-mm-Hg increments, and their ability to predict 6-month outcome.95 A 2013 study by Talving and colleagues found that compliance with this guideline resulted in significantly improved outcomes, providing additional support for this threshold.100 In 2011, Sorrentino and colleagues performed a chi-square analysis on a cohort of 459 TBI patients to identify critical thresholds for cerebral physiological metrics.101 They found that an ICP threshold of 22 mm Hg produced the highest chi-square value for differentiating survival/death and favorable/unfavorable outcome.101 However, because of limitations of this study, the researchers recommended against challenging guidelines on the basis of their findings.101 Additionally, it seems that ideal threshold depends heavily on population analyzed, with different studies producing varying threshold values. Despite this, the BTF revised their guidelines in 2017, now recommending an ICP treatment threshold of 22 mm Hg.13 Additionally, revised guidelines have established a CPP target range of 60–70 mm Hg and now recommend greater focus on this physiological parameter.14 There have yet to be any randomized control trials comparing ICP thresholds.Based on these findings, the BTF published an ICP threshold of 20–25 mm Hg, above which ICP-lowering therapies should be initiated.102 Thus, patients being monitored for ICP should receive routine neurological examinations and CT scans to affirm ICP values.1It should be noted, however, that patients can suffer brain herniation at ICP levels lower than the above-mentioned thresholds. A study by Marshall and colleagues demonstrated that, among patients with pupillary abnormalities, a clinical sign of ICH, ICP values as low as 18 mm Hg were found.103 The added benefit of this metric over the percent time with ICP above threshold is that it considers both duration and intensity of ICP above threshold. Therefore, it better represents the extent of ICH that a patient experiences and is better able to differentiate patients who had ICP greatly exceeding threshold from those who had ICP minimally exceeding threshold. Multiple studies have demonstrated that this dose of ICP is associated with poor 6-month outcome104; however, there is yet to be a consensus on whether it is superior to percent time with ICP above threshold for predicting outcome.A recent concept that has received increasing attention in recent years is time dose of ICP. This metric is defined as the area under the curve (AUC) and above threshold of ICP across a recording period.105 Revised guidelines have established a CPP target range of 60–70 mm Hg and an ICP threshold of >22 mm Hg, beyond which therapeutic treatment is recommended.14Although earlier studies have focused on controlling ICP, recent work suggests concentrating on CPP control.15–17 It has been suggested that this may be, in part, attributable to a failure to take individual phenotype into account and individualize therapeutic management.18 Various studies have shown that individual cerebral physiological responses to TBI are significantly heterogenous.19––23 A 2005 study by Czosnyka and colleagues found that older TBI patients had poorer outcomes in comparison to those who were younger.106 In 2008, Czosnyka and colleagues found that there were sex-related differences in outcome as well.107 They found that females had higher mortality rates, but only in a subgroup of patients <50 years of age.107 When comparing males and females who were >50 years of age, there were no differences.107 Further, Åkerlund and colleagues were able to identify six distinct TBI endotypes based on demographic, physiological, biochemical, and clinical data, and found that consideration of such endotypes significantly improved prognostic modeling.108Over the past decades, our ability to achieve the above-mentioned guideline-based thresholds has drastically improved; however, there has been little to no change in the mortality and morbidity associated with moderate-severe TBI.109 Various candidate genes affiliated with neurodegeneration, neural repair, blood–brain barrier integrity, inflammatory responses, and neurotransmission have been connected to TBI.19 For example, certain polymorphisms in the APOE gene have been shown to be associated with worse outcome in moderate/severe TBI.110 We refer the interested reader to multiple reviews covering the various genetic polymorphisms that have been investigated in relation to TBI.112There is also an extensive body of literature on the role that genetic polymorphisms play in TBI outcome.116 This problem also extends to prognostication, with studies demonstrating that current population-based models accounts for less than half of outcome variance.118 Therefore, it is likely that not only do optimal interventions and treatment targets vary between patients, but also vary across each patient's time in the intensive care unit (ICU).Recent literature has also demonstrated that a significant portion of cerebral insult burden in moderate/severe TBI is impervious to guideline-based therapeutic interventions and that the effects of such interventions vary between different patient subgroups.As mentioned previously, a major problem with the literature is that there is a high degree of variability when it comes to ideal treatment thresholds, likely attributable to differences in populations analyzed. This further points to significant variability in individual responses to TBI. Additionally, most studies that have investigated ICP thresholds grouped patients using mean ICP values calculated over entire monitoring periods. This method does not capture the full picture and blunts the effects of extreme values of ICP. All of these shortcomings of current guideline-based management of TBI drastically demand a new approach, one that more accurately captures and incorporates individual-specific factors.119 The researchers achieved this by plotting CPP against PRx, which revealed a U-shaped curve, and finding the CPP value that most minimized PRx.119 Later works have demonstrated the feasibility of continuously calculating such targets for a person, thus making its application to the clinical setting possible.121 These personalized targets have been reported to have stronger associations with outcome than guideline-based CPP targets.122–125 For example, Aries and colleagues found that patient outcome, when dichotomized into survival/death, was associated with deviation of CPP from continuously updating CPPopt (p < 0.001), and that this association was stronger than that of deviation from the guideline-based CPP target of 60–70 mm Hg.120A promising way forward in moderate-severe TBI management is through the development of individualized therapeutic targets, avoiding the current “one treatment fits all” dogma of guideline-based care. A 2002 study by Steiner and colleagues demonstrated that it was possible to calculate personalized optimal CPP targets (CPPopt) by using the relationship between CPP and cerebrovascular reactivity metrics.127 Derivation of this individualized ICP threshold (iICP) has been achieved by plotting ICP against PRx and finding the ICP value at which PRx remains above +0.20. A patient example of the generation of iICP is presented in 126 Upon receiver operator curve analysis on predictive power for survival, they found that ICP dose (time × intensity) above iICP had greater discriminative ability over doses >20 or 22 mm Hg, with AUC and 95% confidence intervals of 0.81 (0.74–0.87), 0.75 (0.68–0.81), and 0.77 (0.70–0.83), respectively.126 In the second and most recent original work on iICP, Zeiler and colleagues found that iICP could be identified in 65.3% of patients.127 On univariate analysis for survival at 6–12 months post-TBI, ICP dose above iICP  was superior to doses above 20  or 22 mm Hg .127Despite these promising findings, there has been little work done on personalized ICP thresholds, with only two studies published to date. Preliminary work has demonstrated the presence of such a threshold, defining them as the ICP value past which cerebrovascular autoregulation becomes persistently deranged.120 Future work evaluating the feasibility of such derivation is needed. Second, both studies were only able to identify iICP in ∼67% of patients. In addition to being able to continuously derive iICP, a practical algorithm should also improve on this yield through the management of outliers and missing data. Moreover, work evaluating the relationship between percent yield and various patient factors, such as demographics, injury patterns, and treatment, is needed. Third, with the recent findings on the possible superiority of other cerebrovascular reactivity metrics, such as PAx and RAC over PRx for predicting outcome,128––131 further work comparing iICPs derived using the various metrics is needed. Last, additional work evaluating the associations of improved iICP calculations with outcome, that controls for variables known to be associated with outcome, is needed.Further work is required to bring this concept closer to clinical utility. First, both studies to date have used the entire recording period for the derivation of iICP. This does not allow for guiding therapeutic management early in a patient's ICU stay, making it impractical for bedside use. Further, the study by Lazaridis and colleagues utilized manual inspection for the derivation of iICP, and though the study by Zeiler and colleagues utilized a semiautomated derivation technique, a continuously updating derivation is needed in order to make such technology even remotely clinically useful. Such continuously updating derivation is likely achievable by using sliding windows of data, similar to those used in the derivation of continuously updating CPPopt.Over the past decades, there have been many innovations in the field of ICP monitoring. This has facilitated the continuous monitoring of ICP at the bedside and its use in guiding therapeutic management. Unfortunately, despite this and the improvements made in our ability to control ICP, there has been very little change in the poor outcomes associated with moderate-severe TBI. This is because of the one-treatment-fits-all approach of current guideline-based care. The concept of iICP is an exciting and promising way forward in moderate/severe TBI management. However, further work validating its presence, automating its continuous calculation, and evaluating its association with long-term outcome in comparison to guideline-based thresholds is still needed.


World Hypertension Day occurs every year on May 17 to increase awareness and educate the public about the condition. Estimates suggest that 1.28 billion adults aged 30–79 years worldwide are living with hypertension, of whom 46% are unaware that they have the condition and only 42% are diagnosed and treated.Hypertension, also known as high blood pressure, is defined as having a sustained blood pressure of American College of Cardiology and American Heart Association, the International Society of Hypertension, and the National Institute for Health and Care Excellence). However, many aspects associated with hypertension are still poorly understood, such as its underlying causes and contributing factors, and several shortfalls persist, including treatment optimisation and adequacy of blood pressure control.Patient care has evolved substantially in the past few decades, with several guidelines and treatment goals published by different organisations , Louca and colleagues used an extreme gradient boosting (XGBoost) algorithm with 5-fold cross-validation to understand the multifactorial contributors to blood pressure. The authors analysed multimodal data, including genetic, metabolic, laboratory, and demographic features, to predict systolic and diastolic blood pressure measurements in two ethnically diverse populations . The model explained a large proportion of the variance in systolic blood pressure in participants from the TwinsUK cohort  and the Qatari biobank cohort . Traditional risk factors , metabolites , biochemical measures , and dietary intakes of total, trans, and saturated fat were the most predictive features of blood pressure, whereas genetic factors  were not. In another study in eBioMedicine (2022), Reel and colleagues showed that the integration of multi-omics via machine learning had higher discriminatory power than single-omics  data analysis, and correctly classified different forms of endocrine hypertension with high sensitivity and specificity, providing potential diagnostic biomarker combinations for diagnosing secondary hypertension  subtypes.Accurate disease diagnosis is a crucial step in patient care as it substantially improves the likelihood of positive health outcomes. Traditional studies on hypertension have often assessed only single mechanistic pathways via conventional approaches involving statistical tools. However, these approaches have a reduced capacity to capture the multitude and complexity of factors affecting blood pressure , thus limiting the understanding of the condition. The use of machine learning algorithms can facilitate the integration of multi-omics data to aid the discovery of biomarkers for diagnosis. In Hypertension (2020), Wu and colleagues combined recursive feature elimination and XGBoost to build a model predicting clinical outcomes in young patients with hypertension. The performance of the machine learning method  was similar to the prognostic efficacy of the Cox regression model  and higher than the prognostic efficacy of the recalibrated Framingham risk score model . Although the machine learning method used variables that might not be as regularly available as those needed to calculate the other models , some of these variables might represent new predictors of hypertension. In Diagnostics (2019), Chang and colleagues applied recursive feature elimination with cross-validation to identify which input variables provided better predictive power to train four different classification algorithms for hypertension outcomes based on medical data. Of the four classifiers, the XGBoost algorithm produced the best results, with a prediction performance of 94.36% and an area under the receiver operating characteristic curve of 0.927.Machine learning can also substantially contribute to the prognosis of complex conditions because of its ability to process large amounts of complex data. The identification of patterns and prediction of outcomes could inform prognoses and guide disease management or therapy . In Ye and colleagues in the International Journal of Medical Informatics (2020) and Hu and colleagues in BMC Medical Informatics and Decision Making (2023) applied different machine learning tools to identify optimal treatment pathways using electronic health records data. Their findings suggest the utility of predictive models as robust decision-making tools to form risk-adapted, personalised treatment strategies. Oikonomou and colleagues in The Lancet Digital Health (2022) and Inoue and colleagues in the International Journal of Epidemiology (2023) used data from two randomised clinical trials—the SPRINT and ACCORD BP trials—investigating the benefits of intensive systolic blood pressure control versus standard treatment. Oikonomou and colleagues developed a machine-learning-based tool that identified individualised treatment effects using participant-level data for individuals with and without diabetes. Inoue and colleagues used a machine learning technique known as causal forest to identify patients who would benefit the most from blood pressure management. The machine-learning-based high-benefit approach  outperformed the high-risk approach , providing a larger treatment effect. The high-benefit approach might improve treatment effectiveness and population health outcomes without additional resources by identifying people with a high estimated individualised treatment effect, which is a function of individual observable characteristics, regardless of whether they meet the diagnostic criteria for hypertension.Machine learning could also aid the prediction of optimal hypertension treatments and facilitate a personalised medicine approach. Researchers and clinicians could identify how treatment might vary between patients based on individual characteristics, with the potential of increasing treatment effectiveness and improving population health outcomes. HYPERMARKER, was launched to develop and test tools that include machine learning approaches to leverage the use of pharmacometabolomics and identify the most suitable antihypertensive treatment for patients with hypertension. Data will be obtained from well phenotyped cohorts from 11 European countries and the prediction models will be clinically validated through a randomised controlled trial across four sites in Europe. The outcome will be a clinical decision support tool that will allow clinicians to make an informed choice regarding medication for individual patients , thus potentially improving their outcomes.In 2023, an EU-funded project, eBioMedicine. Other issues of clinical applicability might be more difficult to avoid or mitigate and include poor interpretability and potential biases associated with inappropriate design, unrepresentative data, and human biases. Despite these challenges, machine learning has great promise for the future of health care. The clinical implementation of machine learning is evolving and will be pivotal in increasing our comprehension of diseases, such as hypertension, by unravelling the underlying complexities associated with early diagnosis, prognosis, and discovery of potential therapies. As a translational publishing platform, eBioMedicine welcomes research on the discovery and validation of biomarkers and mechanisms of hypertension via machine learning tools. Open access to data, code sharing, and external validation are essential for studies to be considered at eBioMedicine.There are several challenges associated with machine learning tools, such as the need for external validation and transparency for patients, which are strongly encouraged at


Adverse events specific to febuxostat were not observed. Febuxostat effectively reduced serum uric acid in the CKD population without improving endothelial dysfunction. It was able to preserve renal function in the subgroup of patients with CKD and lower serum uric acid level after treatment.Hyperuricemia relates to chronic kidney disease (CKD) progression and impaired endothelial function. Febuxostat is potent and effective for decreasing serum uric acid levels. Information for the effect of febuxostat treatment on markers of endothelial dysfunction and renal injury among patients with CKD remains limited. A total of 84 patients with CKD stages III-IV with asymptomatic hyperuricemia were randomly assigned to either the febuxostat  or the matching control (N = 42) group for 8 weeks. Serum asymmetric dimethylarginine (ADMA), estimated glomerular filtration rate (eGFR), urine albumin, high sensitivity C-reactive protein (hs-CRP), ankle brachial index (ABI) and serum uric acid were measured at baseline and at the end of study. Febuxostat administration significantly reduced the serum uric acid concentration among patients with CKD when compared with control [− 3.40 (95% CI − 4.19 to − 2.62) vs. − 0.35 (95% CI − 0.76 to 0.06) mg/dL; P < 0.001, respectively). No significant difference in the changes in serum ADMA, hs-CRP, eGFR and albuminuria was identified between the two groups. Subgroup analysis among patients with decreased serum uric acid after febuxostat, the estimated GFR change between the febuxostat and the control group showed significant difference at 8 weeks (2.01 (95% CI 0.31 to 3.7) vs. 0.04 (95% CI − 1.52 to 1.61) mL/min/1.73 mTrial registration: Thai Clinical Trials, TCTR20210224005: 24/022021 http://www.thaiclinicaltrials.org/show/TCTR20210224005. Risk factors that are identified and treated at an early stage may prevent or slow disease progression. Hyperuricemia accelerates renal progression and microvascular injury leading to endothelial dysfunction and renal arteriolopathy3. Epidemiologic studies confirmed that increased serum uric levels as an independent risk factor for CKD and cardiovascular disease6. Treatment of hyperuricemia might pose one strategy to prevent CKD progression and endothelial injury.Chronic kidney disease (CKD) has become an important public health problem and a major risk factor for cardiovascular disease7. Febuxostat is a potent and selective xanthine oxidase inhibitor among subjects with hyperuricemia and gout, including those with mild to moderately impaired renal function9. However, all-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol among patients with gout and major cardiovascular diseases10. Low dose febuxostat showed a superior urate-lowering efficacy to that of allopurinol among Asian patients with advanced CKD11. An experimental model suggested that febuxostat improved endothelial function, renal inflammation, tubulointerstitial fibrosis and renal vascular damage13, which might have renal and cardiovascular benefits in the CKD setting. High uric acid also related to endothelial dysfunction independent of traditional cardiovascular risk factors14. Strong clinical evidence to support using xanthine oxidase inhibitors to slow CKD progression and vascular injury remains limited16. Additionally, few studies of febuxostat treatment on renal function and endothelial function have been conducted among patients with advanced CKD and undergoing dialysis18. To fill this gap, we performed a randomized controlled trial among CKD stages 3 to 4 patients to demonstrate the renal function and endothelial function after febuxostat treatment.A systematic review and meta-analysis demonstrated that xanthine oxidase inhibitors delay the decline of renal function and reduce the risk of cardiovascular events among patients with CKDThe study comprised a randomized controlled trial comparing the efficacy between febuxostat and control groups. The study was conducted among patients with CKD treated at Phramongkutklao Hospital between 31 January 2018 and 1 February 2019, with all subjects selected using inclusion criteria. Patients were randomized in blocks of four and allocation concealment, then divided in two groups as shown in Fig. 17.The inclusion criteria included patients with CKD stages III to IV with asymptomatic hyperuricemia, age of 18 years or older, stable dose of all medications including ACEIs or ARBs for blood pressure control at least three months before enrolling and stable renal function within three months before the study. The exclusion criteria comprised active infections, acute kidney injury, advanced malignancy, serious disease, history of hypersensitivity to febuxostat and hospitalization within three months. Based on previous study results, to give 80% power with a two-sided significance level of 0.05 to detect a difference in serum asymmetric dimethylarginine (ADMA) as biomarkers of endothelial dysfunction, a sample size of 38 per treatment group was required to meet the superiority criteria between the febuxostat and placebo groups. Assuming a withdrawal rate of 10%, the target number of patients should be at least 42 in each groupThe data collected before and after in this study, contained relevant information on CKD including diagnostic criteria, complications of disease and other underlying diseases. The history of medications including antihypertensive drugs and physical examination were recorded. The laboratory tests including serum uric acid, blood urea nitrogen, creatinine, calculation of estimated glomerular infiltration rate (GFR) using the 2009 Chronic Kidney Disease Epidemiology Collaboration Equation (CKD-EPI), total cholesterol, low-density lipoprotein and high-density lipoprotein were noted. Participants would receive serum testing for ADMA and high sensitivity C-reactive protein (CRP) by enzyme linked immunosorbent assay. Urine albumin creatinine ratio (UACR) was measured by immunonephelometric assay method after receiving intervention. Ankle brachial index (ABI) was evaluated at baseline using an automatic device . ABI reflected the resistance or compliance of the aorta, femoral artery and tibial artery.The primary outcome was the change of serum ADMA and renal function after eight weeks in the febuxostat group, compared with that of the control group. The secondary outcome was the improving level of UACR after eight weeks. Any adverse events considered to be related to the use of febuxostat were recorded during the study, and any decision was made by the attending physicians during the study. For serious events, febuxostat was discontinued.Measured values of the results were expressed as mean with standard deviation and median with interquartile range (IQR). Comparisons between means of continuous variables were determined using the Student t test, and Mann–Whitney U test as appropriate and between groups of dichotomous variables using the Chi-square test or Fisher's exact test. Paired-sample t tests and Wilcoxon signed-rank test were used for continuous variables and presented by the relative risk of 95% confidence intervals and median change with IQR. Statistical analyses were performed using SPSS Program for Windows, Version 15 . A p < 0.05 was considered statistically significant.The Ethics Committee approved the study , and the research was performed according to the Declaration of Helsinki. Study participants gave consent before participating.A total of 130 patients with CKD stages III to IV were initially screened and 46 were excluded  . In the control group, mean estimated GFR showed no significant change from a baseline of 31.3 ± 15.4 to 31.4 ± 13.1 mL/min/1.73 m2 (P = 0.802). The estimated GFR change between the febuxostat and the control groups significantly differed at eight weeks (2.01 (95% CI 0.31 to 3.7) vs. 0.04 (95% CI − 1.52 to 1.61) mL/min/1.73 m2; P = 0.030, respectively), as shown in Fig. At eight weeks, significant differences were found on mean change of serum uric acid level between the febuxostat and control groups (− 3.4 (95% CI − 4.19 to − 2.62) vs. − 0.35 (95% CI − 0.76 to 0.06) mg/dL, P < 0.001, respectively). However, no significant differences were found on change of renal function, urine albumin, serum ADMA, high sensitivity-CRP and ABI between the two groups as shown in Table Very few adverse events were directly related to febuxostat during the study period (4.7% (2 of 42 patients). One male patient had spontaneous remission of skin rash and another patient had mild abnormal liver function. Our studied patients did not experience any serious side effects of febuxostat during the study, such as major allergic reactions, severe hepatitis or major cardiovascular event.11. However, no significant improvements were observed regarding renal function, albuminuria and endothelial dysfunction after short term febuxostat treatment.In the study, febuxostat at 40 mg daily showed significantly reduced serum uric acid level among patients with CKD stages III to IV and without serious adverse events documented, consistent with a related study9. Recent studies of febuxostat among patients with advanced CKD showed that more than 70 to 80% of these patients could achieve the serum uric acid target less than 6 mg/dL19.Febuxostat constitutes a nonpurine selective xanthine oxidoreductase inhibitor and a high potency for uric acid lowering agent, but limited studies have addressed the efficacy of febuxostat among patients with advanced CKD20. Proposed mechanisms of uric acid and CKD progression induce oxidative stress, renin-angiotensin system activation, renal epithelial-mesenchymal transition and endothelial dysfunction resulting in developing renal arteriolosclerosis and cardiometabolic disease21. Experimental models also indicated that lower serum uric acid with allopurinol or febuxostat improved kidney injury22. Data exist examining the effects of uric acid-lowering therapy on improved renal outcomes from observational studies, small clinical controlled trials and meta-analysis23. Currently, the effect of uric acid-lowering therapy on renal function remains controversial. Recently, two large randomized control trials from the FEATHER study indicated that febuxostat did not slow estimated GFR decline among patients with early CKD and asymptomatic hyperuricemia15. The FREED study also indicated that febuxostat did not improve change of estimated GFR among elderly patients with hyperuricemia24, consistent with our findings. However, the FREED study indicated that febuxostat exhibited a large reduction of serum uric acid levels, and its effect was associated with reduced renal impairment24. Therefore, it exerts a reasonably strong serum uric acid-lowering effect of febuxostat on organ protection. However, the main effects of febuxostat on renal outcome might depend on uric acid lowering effects. Our finding also showed that estimated GFR improved only patients with significantly lower serum uric acid after intervention. Therefore, major effects of febuxostat on renal outcome might be uric acid dependent effects.Observational studies suggest that uric acid is a potential risk factor for developing CKD and cardiovascular progression25. Xanthine oxidase inhibitors produce benefits concerning endothelial function by reducing oxidative stress26. Several randomized controlled studies supported that low dose febuxostat for four to eight weeks improved serum uric acid, oxidative stress, endothelial dysfunction and inflammation markers among patients undergoing hemodialysis27. On the other hand, our study did not confirm a beneficial effect of lowering the markers of endothelial dysfunction (serum ADMA), systemic inflammation (high sensitivity-CRP) and vascular stiffness (ABI) after eight weeks of febuxostat treatments among patients with CKD stages III to IV patients. Low levels of inflammation and endothelial dysfunction at baseline in our CKD population might have been the major effect on treatment outcomes.Endothelial dysfunction is an initial phase in the vascular damage and atherosclerotic process. Hyperuricemia and advanced CKD especially in a dialysis population are related to endothelial dysfunction by impairing the nitric oxide bioavailability and markers of endothelial dysfunction are associated with stage of CKDLimitations encountered in this study included a relatively small sample size; one only half of patients were treated with ACEIs or ARBs and only 3.6% of patients were given sodium–glucose cotransporter 2 inhibitors. The observational period of the present study lasted eight weeks which was relatively short to determine renal outcome; thus, further study with a longer follow-up was needed. We had measurement of biomarkers for endothelial dysfunction  and were unable to longitudinally assess the relationship between changes in endothelial dysfunction and renal function. Therefore, the long term side effects of treatment are needed to be further investigated.In summary, febuxostat effectively reduced serum uric acid among patients with CKD without improvement of endothelial dysfunction and renal function. It was able to preserve renal function in a subgroup of patients with CKD and lower serum uric acid level after treatment. Further study is needed to determine the long term effects of febuxostat on endothelial function and renal progression among patients with advanced CKD.