Cranial Suture Regeneration Mitigates Skull and Neurocognitive Defects in Craniosynostosis.

Craniosynostosis results from premature fusion of the cranial suture(s), which contain mesenchymal stem cells (MSCs) that are crucial for calvarial expansion in coordination with brain growth. Infants with craniosynostosis have skull dysmorphology, increased intracranial pressure, and complications such as neurocognitive impairment that compromise quality of life. Animal models recapitulating these phenotypes are lacking, hampering development of urgently needed innovative therapies. Here, we show that Twist1+/- mice with craniosynostosis have increased intracranial pressure and neurocognitive behavioral abnormalities, recapitulating features of human Saethre-Chotzen syndrome. Using a biodegradable material combined with MSCs, we successfully regenerated a functional cranial suture that corrects skull deformity, normalizes intracranial pressure, and rescues neurocognitive behavior deficits. The regenerated suture creates a niche into which endogenous MSCs migrated, sustaining calvarial bone homeostasis and repair. MSC-based cranial suture regeneration offers a paradigm shift in treatment to reverse skull and neurocognitive abnormalities in this devastating disease.

The Implication of Photodynamic Therapy Applied to the Level of Tumor Resection on Postoperative Cerebral Edema and Intracranial Pressure Changes in Gliomas.

AIM: The aim of our study was to explore the factors influencing cerebral edema and intracranial pressure in glioblastoma multiforme (GBM) patients who undergo photodynamic therapy (PDT) after resection. APPROACH: This was a retrospective controlled study of GBM patients treated with PDT-assisted resections of varying scope from May 2021 to August 2023. The baseline clinical data, cerebral edema volumes, intracranial pressure values, and imaging data of the GBM patients were collected for statistical analysis. RESULTS: A total of 56 GBM patients were included. Thirty of the patients underwent gross total resection (GTR), and the other 26 patients underwent subtotal resection (STR). We found that the cerebral edema volume and the mean intracranial pressure in patients who underwent GTR were lower than those in patients who underwent STR. Moreover, univariate analysis showed that the scope of tumor resection was an independent factor affecting cerebral edema and intracranial pressure after PDT. CONCLUSIONS: Compared with STR, PDT combined with GTR significantly reduced postoperative brain edema volume and intracranial pressure in GBM patients.

Effectiveness of hypertonic saline infusion in management of traumatic brain injury: an updated systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: This study aimed to find out the efficacy of using Hypertonic saline solution (HSS) over mannitol in the management of TBI by comparing their performance in improving different outcomes. METHODS: Electronic databases were searched for randomized controlled trials (RCTs) assessing the impact of HSS vs. mannitol on ICP in patients who suffered TBI. Outcomes of interest were mortality, neurologic functional outcomes, risk ratio (RR) of successful ICP treatment, reduction in ICP after 30-60 and 90-120 min, improvement in cerebral perfusion pressure (CPP) at 30-60 and 90-120 min, and also treatment failure. Evaluations were reported as RR or mean difference (MD) with 95% confidence intervals (CIs) using weighted random-effects models. RESULTS: The analysis included 624 patients from 15 RCTs. HSS infusion had a significant impact on the improvement of CPP at 30-60 min [MD = 5.54, 95% CI (3.04, 8.03),p < 0.001] compared to mannitol. However, results yielded no significant difference between HSS and mannitol in terms of mortality, neurologic functional outcomes, successful ICP treatment, reduction in ICP after 30-60 min and 90-120 min, improvement in CPP at 90-120 min, and treatment failure. CONCLUSION: HSS and mannitol are both effective treatments for elevated ICP due to TBI. However, further research is required to derive a better comparison.

Prospective Observational Study of Volatile Sedation with Sevoflurane After Aneurysmal Subarachnoid Hemorrhage Using the Sedaconda Anesthetic Conserving Device.

BACKGROUND: Volatile sedation is still used with caution in patients with acute brain injury because of safety concerns. We analyzed the effects of sevoflurane sedation on systemic and cerebral parameters measured by multimodal neuromonitoring in patients after aneurysmal subarachnoid hemorrhage (aSAH) with normal baseline intracranial pressure (ICP). METHODS: In this prospective observational study, we analyzed a 12-h period before and after the switch from intravenous to volatile sedation with sevoflurane using the Sedaconda Anesthetic Conserving Device with a target Richmond Agitation Sedation Scale score of - 5 to - 4. ICP, cerebral perfusion pressure (CPP), brain tissue oxygenation (PBrO2), metabolic values of cerebral microdialysis, systemic cardiopulmonary parameters, and the administered drugs before and after the sedation switch were analyzed. RESULTS: We included 19 patients with a median age of 61 years (range 46-78 years), 74% of whom presented with World Federation of Neurosurgical Societies grade 4 or 5 aSAH. We observed no significant changes in the mean ICP (9.3 ± 4.2 vs. 9.7 ± 4.2 mm Hg), PBrO2 (31.0 ± 13.2 vs. 32.2 ± 12.4 mm Hg), cerebral lactate (5.0 ± 2.2 vs. 5.0 ± 1.9 mmol/L), pyruvate (136.6 ± 55.9 vs. 134.1 ± 53.6 µmol/L), and lactate/pyruvate ratio (37.4 ± 8.7 vs. 39.8 ± 9.2) after the sedation switch to sevoflurane. We found a significant decrease in mean arterial pressure (MAP) (88.6 ± 7.6 vs. 86.3 ± 5.8 mm Hg) and CPP (78.8 ± 8.5 vs. 76.6 ± 6.6 mm Hg) after the initiation of sevoflurane, but the decrease was still within the physiological range requiring no additional hemodynamic support. CONCLUSIONS: Sevoflurane appears to be a feasible alternative to intravenous sedation in patients with aSAH without intracranial hypertension, as our study did not show negative effects on ICP, cerebral oxygenation, or brain metabolism. Nevertheless, the risk of a decrease of MAP leading to a consecutive CPP decrease should be considered.

Safety and Effect on Intracranial Pressure of 3% Hypertonic Saline Bolus Via Peripheral Intravenous Catheter for Neurological Emergencies.

BACKGROUND: Elevated intracranial pressure (ICP) is a neurological emergency in patients with acute brain injuries. Such a state requires immediate and effective interventions to prevent potential neurological deterioration. Current clinical guidelines recommend hypertonic saline (HTS) and mannitol as first-line therapeutic agents. Notably, HTS is conventionally administered through central venous catheters (CVCs), which may introduce delays in treatment due to the complexities associated with CVC placement. These delays can critically affect patient outcomes, necessitating the exploration of more rapid therapeutic avenues. This study aimed to investigate the safety and effect on ICP of administering rapid boluses of 3% HTS via peripheral intravenous (PIV) catheters. METHODS: A retrospective cohort study was performed on patients admitted to Sisters of Saint Mary Health Saint Louis University Hospital from March 2019 to September 2022 who received at least one 3% HTS bolus via PIV at a rate of 999 mL/hour for neurological emergencies. Outcomes assessed included complications related to 3% HTS bolus and its effect on ICP. RESULTS: Of 216 3% HTS boluses administered in 124 patients, complications occurred in 8 administrations (3.7%). Pain at the injection site (4 administrations; 1.9%) and thrombophlebitis (3 administrations; 1.4%) were most common. The median ICP reduced by 6 mm Hg after 3% HTS bolus administration (p < 0.001). CONCLUSIONS: Rapid bolus administration of 3% HTS via PIV catheters presents itself as a relatively safe approach to treat neurological emergencies. Its implementation could provide an invaluable alternative to the traditional CVC-based administration, potentially minimizing CVC-associated complications and expediting life-saving interventions for patients with neurological emergencies, especially in the field and emergency department settings.

Comparison of 4.54% hypertonic saline and 20% mannitol for brain relaxation during auditory brainstem implantation in pediatric patients: a single-center retrospective observational cohort study.

BACKGROUND: Mannitol is frequently utilized to achieve intracranial brain relaxation during the retrosigmoid approach for auditory brainstem implantation (ABI). Hypertonic saline (HS) is an alternative for reducing intracranial pressure; however, its application during ABI surgery remains under-investigated. We aimed to compare the efficacy and safety between HS and mannitol for maintaining brain relaxation. METHODS: This single-center retrospective cohort study included pediatric patients undergoing ABI surgery from September 2020 to January 2022 who received only 4.54% HS or 20% mannitol for brain relaxation. The analysis involved initial doses, subsequent doses, and dosing intervals of the two hyperosmolar solutions, as well as the time elapsed from meningeal opening to the first ABI electrode placement attempt. Additionally, the analysis encompassed electrolyte testing, hemodynamic variables, urine output, blood transfusion, second surgeries, adverse events, intensive care unit length of stay, and 30-day mortality. RESULTS: We analyzed 68 consecutive pediatric patients; 26 and 42 in the HS and mannitol groups, respectively. The HS group exhibited a reduced rate of supplementary use (7.7% vs. 31%) and lower total urine volume. Perioperative outcomes, mortality, and length of intensive care unit stay did not exhibit significant between-group differences, despite transient increases in blood sodium and chloride observed within 2 h after HS infusion. CONCLUSIONS: In pediatric ABI surgery, as an osmotherapy for cerebral relaxation, 4.54% HS demonstrated a lower likelihood of necessitating additional supplementation than 20% mannitol. Furthermore, the diuretic effect of HS was weak and the increase in electrolyte levels during surgery was temporary and slight.

Anesthesia for traumatic brain injury.

PURPOSE OF REVIEW: Traumatic brain injury (TBI) presents complex clinical challenges, requiring a nuanced understanding of its pathophysiology and current management principles to improve patient outcomes. Anesthetists play a critical role in care and need to stay updated with recent evidence and trends to ensure high-quality treatment. The Brain Trauma Foundation Guidelines, last updated in 2016, have shown moderate adherence, and much of the current management relies on expert opinions. This literature review synthesizes the current evidence and provides insights into the role of anesthetists in TBI management. RECENT FINDINGS: Recent literature has emphasized the importance of tailored anesthetic management principles in treating TBI, focusing on minimizing secondary brain injury during neurosurgical interventions or extracranial surgery. Emerging trends include individualized intracranial pressure approaches and multimodal neuromonitoring for comprehensive assessment of cerebral physiology. SUMMARY: Anesthesia for TBI patients requires a comprehensive approach that balances anesthetic goals with the unique pathophysiological factors of brain injury. Despite recent research expanding our understanding, challenges remain in standardizing protocols and addressing individual patient response variability. Adherence to established management principles, personalized approaches, and ongoing research is crucial for improving the outcomes.

A Post Hoc Analysis of Osmotherapy Use in the Erythropoietin in Traumatic Brain Injury Study-Associations With Acute Kidney Injury and Mortality.

OBJECTIVES: Mannitol and hypertonic saline are used to treat raised intracerebral pressure in patients with traumatic brain injury, but their possible effects on kidney function and mortality are unknown. DESIGN: A post hoc analysis of the erythropoietin trial in traumatic brain injury (ClinicalTrials.gov NCT00987454) including daily data on mannitol and hypertonic saline use. SETTING: Twenty-nine university-affiliated teaching hospitals in seven countries. PATIENTS: A total of 568 patients treated in the ICU for 48 hours without acute kidney injury of whom 43 (7%) received mannitol and 170 (29%) hypertonic saline. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We categorized acute kidney injury stage according to the Kidney Disease Improving Global Outcome classification and defined acute kidney injury as any Kidney Disease Improving Global Outcome stage-based changes from the admission creatinine. We tested associations between early (first 2 d) mannitol and hypertonic saline and time to acute kidney injury up to ICU discharge and death up to 180 days with Cox regression analysis. Subsequently, acute kidney injury developed more often in patients receiving mannitol (35% vs 10%; p < 0.001) and hypertonic saline (23% vs 10%; p < 0.001). On competing risk analysis including factors associated with acute kidney injury, mannitol (hazard ratio, 2.3; 95% CI, 1.2-4.3; p = 0.01), but not hypertonic saline (hazard ratio, 1.6; 95% CI, 0.9-2.8; p = 0.08), was independently associated with time to acute kidney injury. In a Cox model for predicting time to death, both the use of mannitol (hazard ratio, 2.1; 95% CI, 1.1-4.1; p = 0.03) and hypertonic saline (hazard ratio, 1.8; 95% CI, 1.02-3.2; p = 0.04) were associated with time to death. CONCLUSIONS: In this post hoc analysis of a randomized controlled trial, the early use of mannitol, but not hypertonic saline, was independently associated with an increase in acute kidney injury. Our findings suggest the need to further evaluate the use and choice of osmotherapy in traumatic brain injury.

The neuroprotective effects of AMN082 on neuronal apoptosis in rats after traumatic brain injury.

BACKGROUND: The aim of this study was to investigate whether AMN082 exerts its neuroprotective effect by attenuating glutamate receptor-associated neuronal apoptosis and improving functional outcomes after traumatic brain injury (TBI). METHODS: Anesthetized male Sprague-Dawley rats were divided into the sham-operated, TBI + vehicle, and TBI + AMN082 groups. AMN082 (10 mg/kg) was intraperitoneally injected 0, 24, or 48 h after TBI. In the 120 min after TBI, heart rate, mean arterial pressure, intracranial pressure (ICP), and cerebral perfusion pressure (CPP) were continuously measured. Motor function, the infarct volume, neuronal nitrosative stress-associated apoptosis, and N-methyl-D-aspartate receptor 2A (NR2A) and NR2B expression in the pericontusional cortex were measured on the 3rd day after TBI. RESULTS: The results showed that the AMN082-treated group had a lower ICP and higher CPP after TBI. TBI-induced motor deficits, the increase in infarct volume, neuronal apoptosis, and 3-nitrotyrosine and inducible nitric oxide synthase expression in the pericontusional cortex were significantly improved by AMN082 therapy. Simultaneously, AMN082 increased NR2A and NR2B expression in neuronal cells. CONCLUSIONS: We concluded that intraperitoneal injection of AMN082 for 3 days may ameliorate TBI by attenuating glutamate receptor-associated nitrosative stress and neuronal apoptosis in the pericontusional cortex. We suggest that AMN082 administration in the acute stage may be a promising strategy for TBI.

Ketamine in acute phase of severe traumatic brain injury "an old drug for new uses?"

Maintaining an adequate level of sedation and analgesia plays a key role in the management of traumatic brain injury (TBI). To date, it is unclear which drug or combination of drugs is most effective in achieving these goals. Ketamine is an agent with attractive pharmacological and pharmacokinetics characteristics. Current evidence shows that ketamine does not increase and may instead decrease intracranial pressure, and its safety profile makes it a reliable tool in the prehospital environment. In this point of view, we discuss different aspects of the use of ketamine in the acute phase of TBI, with its potential benefits and pitfalls.

Elevated Intracranial Pressure Associated With Exogenous Hormonal Therapy Used for Gender Affirmation.

BACKGROUND: Addison disease, corticosteroid withdrawal, and taking synthetic growth hormone have been linked with development of intracranial hypertension, but there is still debate on whether administration of other exogenous hormones plays a role in precipitating elevated pressure. The growing use of hormonal therapy for gender affirmation provides an opportunity to explore this possibility. METHODS: All transgender patients taking exogenous hormones for female-to-male (FTM) and male-to-female (MTF) transitions who were diagnosed with intracranial hypertension at Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital and Beth Israel Deaconess Medical Center between August 2014 and November 2018 were included in a retrospective review. Visual acuity, type, and dose of exogenous hormone, visual field testing, clinical exam, results of neuroimaging and lumbar puncture, and treatment modalities were catalogued and analyzed. RESULTS: Six transgender individuals were identified. Five were FTM, with an average hormone treatment time of 18.4 months, and one was MTF who had been treated with hormones for 4 years. The average age of all patients was 23.5 years. The average time between onset of symptoms and presentation was 5 months. Fifty percent of the patients reported pulse-synchronous tinnitus, 83% reported positional headache, 33% reported transient visual obscurations, and 16% reported diplopia. Lumbar punctures performed on 4 of the patients revealed elevated opening pressures and normal cerebrospinal fluid constituents. MRI findings consistent with elevated intracranial pressure (ICP) were present in the other 2 patients in whom lumbar puncture was unsuccessful. Four patients were treated with acetazolamide and one was treated with topiramate, with an average follow-up time of 15.7 months. All patients demonstrated bilateral optic disc swelling, and all maintained normal acuity and color vision. Performance on visual field testing was not significantly affected in any patient. CONCLUSIONS: This is the largest reported series to date of gender-transitioning patients with intracranial hypertension, including one novel MTF conversion. These observations warrant further investigation into the possible link of exogenous hormonal therapy and elevated ICP and any mechanisms or confounders underlying this potential association.

Temporal effects of barbiturate coma on intracranial pressure and compensatory reserve in children with traumatic brain injury.

BACKGROUND: The aim was to study the effects of barbiturate coma treatment (BCT) on intracranial pressure (ICP) and intracranial compensatory reserve (RAP index) in children (< 17 years of age) with traumatic brain injury (TBI) and refractory intracranial hypertension (RICH). METHODS: High-resolution monitoring data were used to study the effects of BCT on ICP, mean arterial pressure (MAP), cerebral perfusion pressure (CPP), and RAP index. Four half hour long periods were studied: before bolus injection and at 5, 10, and 24 hours thereafter, respectively, and a fifth tapering period with S-thiopental between < 100 and < 30 µmol/L. S-thiopental concentrations and administered doses were registered. RESULTS: Seventeen children treated with BCT 2007-2017 with high-resolution data were included; median age 15 (range 6-17) and median Glasgow coma score 7 (range 3-8). Median time from trauma to start of BCT was 44.5 h (range 2.5-197.5) and from start to stop 99.0 h (range 21.0-329.0). Median ICP was 22 (IQR 20-25) in the half hour period before onset of BCT and 16 (IQR 11-20) in the half hour period 5 h later (p = 0.011). The corresponding figures for CPP were 65 (IQR 62-71) and 63 (57-71) (p > 0.05). The RAP index was in the half hour period before onset of BCT 0.6 (IQR 0.1-0.7), in the half hour period 5 h later 0.3 (IQR 0.1-0.7) (p = 0.331), and in the whole BCT period 0.3 (IQR 0.2-0.4) (p = 0.004). Eighty-two percent (14/17) had favorable outcome (good recovery = 8 patients and moderate disability = 6 patients). CONCLUSION: BCT significantly reduced ICP and RAP index with preserved CPP. BCT should be considered in case of RICH.

Effects of propofol on intracranial pressure and prognosis in patients with severe brain diseases undergoing endotracheal suctioning.

BACKGROUND: To investigate whether the administration of intravenous propofol before endotracheal suctioning (ES) in patients with severe brain disease can reduce the sputum suction response, improve prognosis, and accelerate recovery. METHODS: A total of 208 severe brain disease patients after craniocerebral surgery were enrolled in the study. The subjects were randomly assigned to the experimental group (n = 104) and the control group (n = 104). The experimental group was given intravenous propofol (10 ml propofol with 1 ml 2% lidocaine), 0.5-1 mg/kg, before ES, while the control group was subjected to ES only. Changes in vital signs, sputum suction effect, the fluctuation range of intracranial pressure (ICP) before and after ES, choking cough response, short-term complications, length of stay, and hospitalization cost were evaluated. Additionally, the Glasgow Outcome Scale (GOS) prognosis score was obtained at 6 months after the operation. RESULTS: At the baseline, the characteristics of the two groups were comparable (P > 0.05). The increase of systolic blood pressure after ES was higher in the control group than in the experimental group (P < 0.05). The average peak value of ICP in the experimental group during the suctioning (15.57 ± 12.31 mmHg) was lower than in the control group (18.24 ± 8.99 mmHg; P < 0.05). The percentage of patients experiencing cough reaction- during suctioning in the experimental group was lower than in the control group (P < 0.05), and the fluctuation range of ICP was increased (P < 0.0001). The effect of ES was achieved in both groups. The incidence of short-term complications in the two groups was comparable (P > 0.05). At 6 months after the surgery, the GOS scores were significantly higher in the experimental than in the control group (4-5 points, 51.54% vs. 32.64%; 1-3 points, 48.46% vs. 67.36%; P < 0.05). There was no significant difference in the length of stay and hospitalization cost between the two groups. CONCLUSIONS: Propofol sedation before ES could reduce choking cough response and intracranial hypertension response. The use of propofol was safe and improved the long-term prognosis. The study was registered in the Chinese Clinical Trial Registry on May 16, 2015 (ChiCTR-IOR-15006441).

Standardized Volume Dosing Protocol of 23.4% Hypertonic Saline for Pediatric Critical Care: Initial Experience.

Background: Standardized volume dosing of 23.4% hypertonic saline (HTS) exists for adults, but the concentration, dosing and administration of HTS in pediatrics is variable. With emerging pediatric experience of 23.4% HTS, a standard volume dose approach may be helpful. Objective: To describe initial experience with a standardized 23.4% HTS weight-based volume dosing protocol of 10, 20, or 30 mL in the pediatric intensive care unit. Methods: Standard volume doses of 23.4% HTS were developed from weight dosing equivalents of 3% HTS. Pre and post sodium and intracranial pressure (ICP) measurements were compared with paired t-test or Wilcoxon rank-sum test. The site of administration and complications were noted. Results: A total of 16 pediatric patients received 37 doses of 23.4% HTS, with the smallest patient weighing 11 kg. For protocol compliance, 17 doses (46%) followed recommended dosing, 19 were less volume than recommended (51%), and 1 dose (3%) was more than recommended. Mean increase in sodium was 3.5 mEq/L (95% CI = 2-5 mEq/L); P < 0.0001. The median decrease in ICP was 10.5 mm Hg (interquartile range [IQR] 8.3-19.5) for a 37% (IQR 25%-64%) reduction. Most doses were administered through central venous access, although peripheral intravenous administrations occurred in 4 patients without complication. Conclusion and Relevance: Three standard-volume dose options of 23.4% HTS based on weight increases sodium and reduces ICP in pediatric patients. Standard-volume doses may simplify weight-based dosing, storage and administration for pediatric emergencies, although the optimum dose, and safety of 23.4% HTS in children remains unknown.

Hypertonic saline versus other intracranial pressure-lowering agents for people with acute traumatic brain injury.

BACKGROUND: Increased intracranial pressure has been shown to be strongly associated with poor neurological outcomes and mortality for patients with acute traumatic brain injury. Currently, most efforts to treat these injuries focus on controlling the intracranial pressure. Hypertonic saline is a hyperosmolar therapy that is used in traumatic brain injury to reduce intracranial pressure. The effectiveness of hypertonic saline compared with other intracranial pressure-lowering agents in the management of acute traumatic brain injury is still debated, both in the short and the long term. OBJECTIVES: To assess the comparative efficacy and safety of hypertonic saline versus other intracranial pressure-lowering agents in the management of acute traumatic brain injury. SEARCH METHODS: We searched Cochrane Injuries' Specialised Register, CENTRAL, PubMed, Embase Classic+Embase, ISI Web of Science: Science Citation Index and Conference Proceedings Citation Index-Science, as well as trials registers, on 11 December 2019. We supplemented these searches with searches of four major Chinese databases on 19 September 2018. We also checked bibliographies, and contacted trial authors to identify additional trials. SELECTION CRITERIA: We sought to identify all randomised controlled trials (RCTs) of hypertonic saline versus other intracranial pressure-lowering agents for people with acute traumatic brain injury of any severity. We excluded cross-over trials as incompatible with assessing long-term outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results to identify potentially eligible trials and extracted data using a standard data extraction form. Outcome measures included: mortality at end of follow-up (all-cause); death or disability (as measured by the Glasgow Outcome Scale (GOS)); uncontrolled intracranial pressure (defined as failure to decrease the intracranial pressure to target and/or requiring additional intervention); and adverse events e.g. rebound phenomena; pulmonary oedema; acute renal failure during treatment). MAIN RESULTS: Six trials, involving data from 287 people, met the inclusion criteria. The majority of participants (91%) had a diagnosis of severe traumatic brain injury. We had concerns about particular domains of risk of bias in each trial, as physicians were not reliably blinded to allocation, two trials contained participants with conditions other than traumatic brain injury and in one trial, we had concerns about missing data for important outcomes. The original protocol was available for only one trial and other trials (where registered) were registered retrospectively. Meta-analysis for both the primary outcome (mortality at final follow-up) and for 'poor outcome' as per conventionally dichotomised GOS criteria, was only possible for two trials. Synthesis of long-term outcomes was inhibited by the fact that two trials ceased data collection within two hours of a single bolus dose of an intracranial pressure-lowering agent and one at discharge from the intensive care unit (ICU). Only three trials collected data after participants were released from hospital, one of which did not report mortality and reported a 'poor outcome' by GOS criteria in an unconventional way. Substantial missing data in a key trial meant that in meta-analysis we report 'best-case' and 'worst-case' estimates alongside available case analysis. In no scenario did we discern a clear difference between treatments for either mortality or poor neurological outcome. Due to variation in modes of drug administration (including whether it followed or did not follow cerebrospinal fluid (CSF) drainage, as well as different follow-up times and ways of reporting changes in intracranial pressure, as well as no uniform definition of 'uncontrolled intracranial pressure', we did not perform meta-analysis for this outcome and report results narratively, by individual trial. Trials tended to report both treatments to be effective in reducing elevated intracranial pressure but that hypertonic saline had increased benefits, usually adding that pretreatment factors need to be considered (e.g. serum sodium and both system and brain haemodynamics). No trial provided data for our other outcomes of interest. We consider evidence quality for all outcomes to be very low, as assessed by GRADE; we downgraded all conclusions due to imprecision (small sample size), indirectness (due to choice of measurement and/or selection of participants without traumatic brain injury), and in some cases, risk of bias and inconsistency. Only one of the included trials reported data on adverse effects; a rebound phenomenon, which was present only in the comparator group (mannitol). None of the trials reported data on pulmonary oedema or acute renal failure during treatment. On the whole, trial authors do not seem to have rigorously sought to collect data on adverse events. AUTHORS' CONCLUSIONS: This review set out to find trials comparing hypertonic saline to a potential range of other intracranial pressure-lowering agents, but only identified trials comparing it with mannitol or mannitol in combination with glycerol. Based on limited data, there is weak evidence to suggest that hypertonic saline is no better than mannitol in efficacy and safety in the long-term management of acute traumatic brain injury. Future research should be comprised of large, multi-site trials, prospectively registered, reported in accordance with current best practice. Trials should investigate issues such as the type of traumatic brain injury suffered by participants and concentration of infusion and length of time over which the infusion is given.

Basic Fibroblast Growth Factor (bFGF) Protects the Blood-Brain Barrier by Binding of FGFR1 and Activating the ERK Signaling Pathway After Intra-Abdominal Hypertension and Traumatic Brain Injury.

BACKGROUND Intra-abdominal hypertension (IAH) is associated with high morbidity and mortality. IAH leads to intra-abdominal tissue damage and causes dysfunction in distal organs such as the brain. The effect of a combined injury due to IAH and traumatic brain injury (TBI) on the integrity of the blood-brain barrier (BBB) has not been investigated. MATERIAL AND METHODS Intracranial pressure (ICP) monitoring, brain water content, EB permeability detection, immunofluorescence staining, real-time PCR, and Western blot analysis were used to examine the effects of IAH and TBI on the BBB in rats, and to characterize the protective effects of basic fibroblast growth factor (bFGF) on combined injury-induced BBB damage. RESULTS Combined injury from IAH and TBI to the BBB resulted in brain edema and increased intracranial pressure. The effects of bFGF on alleviating the rat BBB injuries were determined, indicating that bFGF regulated the expression levels of the tight junction (TJ), adhesion junction (AJ), matrix metalloproteinase (MMP), and IL-1ß, as well as reduced BBB permeability, brain edema, and intracranial pressure. Moreover, the FGFR1 antagonist PD 173074 and the ERK antagonist PD 98059 decreased the protective effects of bFGF. CONCLUSIONS bFGF effectively protected the BBB from damage caused by combined injury from IAH and TBI, and binding of FGFR1 and activation of the ERK signaling pathway was involved in these effects.

The impact of hypertonic saline on cerebrovascular reactivity and compensatory reserve in traumatic brain injury: an exploratory analysis.

BACKGROUND: Intravenous hypertonic saline is utilized commonly in critical care for treatment of acute or refractory elevations of intracranial pressure (ICP) in traumatic brain injury (TBI) patients. Though there is a clear understanding of the general physiological effects of a hypertonic saline solution over long periods of time, smaller epoch effects of hypertonic saline (HTS) have not been thoroughly analyzed. The aim of this study was to perform a direct evaluation of the high-frequency response of HTS on the cerebrovascular physiological responses in TBI. METHODS: We retrospectively reviewed our prospectively maintained adult TBI database for those with archived high-frequency cerebral physiology and available HTS treatment information. We evaluated different epochs of physiology around HTS bolus dosing, comparing pre- with post-HTS. We assessed for changes in slow fluctuations in ICP, pulse amplitude of ICP (AMP), cerebral perfusion pressure (CPP), mean arterial pressure (MAP), cerebrovascular reactivity (as measured through pressure reactivity index (PRx)), and cerebral compensatory reserve (correlation (R) between AMP (A) and ICP (P)). Comparisons of mean measures and percentage time above clinically relevant thresholds for the physiological parameters were compared pre- and post-HTS using descriptive statistics and Mann-Whitney U testing. We assessed for subgroups of physiological responses using latent profile analysis (LPA). RESULTS: Fifteen patients underwent 69 distinct bolus infusions of hypertonic saline. Apart from the well-documented decrease in ICP, there was also a reduction in AMP. The analysis of cerebrovascular reactivity response to HTS solution had two main effects. For patients with grossly impaired cerebrovascular reactivity pre-HTS (PRx > + 0.30), HTS bolus led to improved reactivity. However, for those with intact cerebrovascular reactivity pre-HTS (PRx < 0), HTS bolus demonstrated a trend towards more impaired reactivity. This indicates that HTS has different impacts, dependent on pre-bolus cerebrovascular status. There was no significant change in metrics of cerebral compensatory reserve. LPA failed to demonstrate any subgroups of physiological responses to HTS administration. CONCLUSIONS: The direct decrease in ICP and AMP confirms that a bolus dose of a HTS solution is an effective therapeutic agent for intracranial hypertension. However, in patients with intact autoregulation, hypertonic saline may impair cerebral hemodynamics. These findings regarding cerebrovascular reactivity remain preliminary and require further investigation.

Hypertensive Response to Ischemic Stroke in the Normotensive Wistar Rat.

Background and Purpose- Over 80% of ischemic stroke patients show an abrupt increase in arterial blood pressure in the hours and days following ischemic stroke. Whether this poststroke hypertension is beneficial or harmful remains controversial and the underlying physiological basis is unclear. Methods- To investigate the dynamic cardiovascular response to stroke, adult Wistar rats (n=5-8 per group, 393±34 g) were instrumented with telemeters to blood pressure, intracranial pressure, renal sympathetic nerve activity, and brain tissue oxygen in the predicted penumbra (Po2). After 2 weeks of recovery, cardiovascular signals were recorded for a 3-day baseline period, then ischemic stroke was induced via transient middle cerebral artery occlusion, or sham surgery. Cardiovascular signals were then recorded for a further 10 days, and the functional sensorimotor recovery assessed using the cylinder and sticky dot tests. Results- Baseline values of all variables were similar between groups. Compared to sham, in the 2 days following stroke middle cerebral artery occlusion produced an immediate, transient rise above baseline in mean blood pressure (21±3 versus 2±4 mm Hg; P<0.001), renal sympathetic nerve activity (54±11% versus 7±4%; P=0.006), and cerebral perfusion pressure (12±5 versus 1±4; P≤0.001). Intracranial pressure increased more slowly, peaking 3 days after middle cerebral artery occlusion (14±6 versus -1±1 mm Hg; P<0.001). Treating with the antihypertensive agent nifedipine after stroke (1.5-0.75 mg/kg per hour SC) ameliorated poststroke hypertension (12±3 mm Hg on day 1; P=0.041), abolished the intracranial pressure increase (3±1; P<0.001) and reduced cerebral perfusion pressure (10±3 mm Hg; P=0.017). Preventing poststroke hypertension affected neither the recovery of sensorimotor function nor infarct size. Conclusions- These findings suggest that poststroke hypertension is immediate, temporally matched to an increase in sympathetic outflow, and elevates cerebral perfusion pressure for several days after stroke, which may enhance cerebral perfusion. Preventing poststroke hypertension does not appear to worsen prognosis after stroke in young, normotensive, and otherwise healthy rats. Visual Overview- An online visual overview is available for this article.

Topiramate is more effective than acetazolamide at lowering intracranial pressure.

BACKGROUND: The management of idiopathic intracranial hypertension focuses on reducing intracranial pressure to preserve vision and reduce headaches. There is sparse evidence to support the use of some of the drugs commonly used to manage idiopathic intracranial hypertension, therefore we propose to evaluate the efficacy of these drugs at lowering intracranial pressure in healthy rats. METHODS: We measured intracranial pressure in female rats before and after subcutaneous administration of acetazolamide, topiramate, furosemide, amiloride and octreotide at clinical doses (equivalent to a single human dose) and high doses (equivalent to a human daily dose). In addition, we measured intracranial pressure after oral administration of acetazolamide and topiramate. RESULTS: At clinical and high doses, subcutaneous administration of topiramate lowered intracranial pressure by 32% ( p = 0.0009) and 21% ( p = 0.015) respectively. There was no significant reduction in intracranial pressure noted with acetazolamide, furosemide, amiloride or octreotide at any dose. Oral administration of topiramate significantly lowered intracranial pressure by 22% ( p = 0.018), compared to 5% reduction with acetazolamide ( p = >0.999). CONCLUSION: Our in vivo studies demonstrated that both subcutaneous and oral administration of topiramate significantly lowers intracranial pressure. Other drugs tested, including acetazolamide, did not significantly reduce intracranial pressure. Future clinical trials evaluating the efficacy and side effects of topiramate in idiopathic intracranial hypertension patients would be of interest.

Cerebral metabolism is not affected by moderate hyperventilation in patients with traumatic brain injury.

BACKGROUND: Hyperventilation-induced hypocapnia (HV) reduces elevated intracranial pressure (ICP), a dangerous and potentially fatal complication of traumatic brain injury (TBI). HV decreases the arteriolar diameter of intracranial vessels, raising the risk of cerebral ischemia. The aim of this study was to characterize the effects of moderate short-term HV in patients with severe TBI by using concomitant monitoring of cerebral metabolism, brain tissue oxygen tension (PbrO2), and cerebral hemodynamics with transcranial color-coded duplex sonography (TCCD). METHODS: This prospective trial was conducted between May 2014 and May 2017 in the surgical intensive care unit (ICU) at the University Hospital of Zurich. Patients with nonpenetrating TBI older than 18 years of age with a Glasgow Coma Scale (GCS) score < 9 at presentation and with ICP monitoring, PbrO2, and/or microdialysis (MD) probes during ICU admission within 36 h after injury were included in our study. Data collection and TCCD measurements were performed at baseline (A), at the beginning of moderate HV (C), after 50 min of moderate HV (D), and after return to baseline (E). Moderate HV was defined as arterial partial pressure of carbon dioxide 4-4.7 kPa. Repeated measures analysis of variance was used to compare variables at the different time points, followed by post hoc analysis with Bonferroni adjustment as appropriate. RESULTS: Eleven patients (64% males, mean age 36 ± 14 years) with an initial median GCS score of 7 (IQR 3-8) were enrolled. During HV, ICP and mean flow velocity (CBFV) in the middle cerebral artery decreased significantly. Glucose, lactate, and pyruvate in the brain extracellular fluid did not change significantly, whereas PbrO2 showed a statistically significant reduction but remained within the normal range. CONCLUSION: Moderate short-term hyperventilation has a potent effect on the cerebral blood flow, as shown by TCCD, with a concomitant ICP reduction. Under the specific conditions of this study, this degree of hyperventilation did not induce pathological alterations of brain metabolites and oxygenation. TRIAL REGISTRATION: NCT03822026 . Registered on 30 January 2019.