Dose Of Mannitol Research Articles

The Cough Response to Inhaled Mannitol in Healthy Subjects

PurposeInhaled mannitol induces bronchoconstriction and cough. This study aimed to describe the cough response to mannitol among healthy adult subjects.Methods125 healthy subjects (aged 18–82 years, 52% females, 50% skin prick test positive) underwent a mannitol test. The coughs were recorded both simultaneously and afterwards from video recordings by two researchers. Three indices were evaluated: The cumulative number of coughs per cumulative dose of mannitol (CDR), cumulative provocative dose of mannitol to cause at least 5 coughs, and the maximal number of coughs provoked by any single mannitol dose. The test was repeated in 26 subjects after 3–7 days.ResultsCDR showed the best repeatability with an intraclass correlation coefficient of 0.829. Gender was the only characteristics that associated with the cough response: The median CDR was 2.53 (interquartile range 0.45–7.01) coughs/100 mg among females and 0.787 (0.0–3.29) coughs/100 mg among males (p = 0.002). The interquartile range upper limits were defined as the cut-off limits for a normal response. The threshold for a statistically significant change in CDR was 6.26 coughs/100 mg. There was a close correlation between simultaneous- and video-assessed CDR (intraclass correlation coefficient 0.985).ConclusionFemales cough more than males in response to mannitol. CDR is the most suitable index to describe the cough responsiveness. The repeatability of the response is good. Video recording of the coughs is not mandatory. The cut-off limits for a normal cough response to mannitol were provided.

Assessment of Mannitol-Induced Chronic Blood-Brain Barrier Dysfunction In Vivo Using Magnetic Resonance.

The blood-brain barrier (BBB) is essential for protection and plays a crucial role in chronic neurological disorders like small-vessel disease and Alzheimer's disease. Its complexity poses significant challenges for effective diagnostics and treatments, highlighting the need for novel animal models and comprehensive BBB dysfunction studies. This study investigates chronic BBB dysfunction induction using osmotic disruption via mannitol in healthy adult male Sprague Dawley rats over 12 weeks. Group 1 received 1 bolus/week (2.0 g/kg), Group 2 received 3 boluses/week (1.5 g/kg), and Group 3 received 3 boluses/week (2.5 g/kg). BBB dysfunction was assessed using gadolinium (Gd) infusion and MRI to evaluate location, severity, evolution, and persistence. MR spectroscopy (MRS) examined the brain metabolism changes due to intravenous mannitol, with T2-weighted MRI assessing brain lesions. Biomarkers of neuroinflammation were analyzed in the highest mannitol dose group. Our data show chronic BBB dysfunction primarily in the cortex, hippocampus, and striatum, but not in the corpus callosum of rats under periodic mannitol dosing in groups 1 and 2. MRS identified a distinctive metabolite signature, including changes in alanine, choline, and N-acetyl aspartate in the striatum of Group 1. No significant differences were found in the serum levels of all pro- and anti-inflammatory cytokines analyzed in the high-dose Group 3. This study underscores the feasibility and implications of using osmotic disruption to model chronic BBB dysfunction, offering insights for future neuroprotection and therapeutic strategies research.

Urinary excretion of gluten immunoreactive peptides as an indicator of gastrointestinal function after fasting and dietary provocation in healthy volunteers.

Understanding intestinal permeability is paramount for elucidating gastrointestinal health and pathology. The size and nature of the molecule traversing the intestinal barrier offer crucial insights into various acute and chronic diseases, as well as the evolution of some conditions. This study aims to assess the urinary excretion kinetics of gluten immunogenic peptides (u-GIP), a unique class of dietary peptides detectable in urine, in volunteers under controlled dietary conditions. This evaluation should be compared to established probes like lactulose, a non-digestible disaccharide indicative of paracellular permeability, and mannitol, reflecting transcellular permeability. Fifteen participants underwent simultaneous ingestion of standardized doses of gluten (10 g), lactulose (10 g), and mannitol (1 g) under fasting conditions for at least 8 hours pre-ingestion and during 6 hours post-ingestion period. Urine samples were collected over specified time intervals. Excretion patterns were analyzed, and correlations between the lactulose-to-mannitol ratio (LMR) and u-GIP parameters were assessed. The majority of u-GIP were detected within the first 12 hours post-ingestion. Analysis of the variability in cumulative excretion across two sample collection ranges demonstrated that lactulose and u-GIP exhibited similar onset and excretion dynamics, although GIP reached its maximum peak earlier than either lactulose or mannitol. Additionally, a moderate correlation was observed between the LMR and u-GIP parameters within the longest urine collection interval, indicating potential shared characteristics among permeability pathways. These findings suggest that extending urine collection beyond 6 hours may enhance data reliability. This study sheds light on the temporal dynamics of u-GIP in comparison to lactulose and mannitol, established probes for assessing intestinal permeability. The resemblance between u-GIP and lactulose excretion patterns aligns with the anticipated paracellular permeability pathway. The capacity to detect antigenic food protein fragments in urine opens novel avenues for studying protein metabolism and monitoring pathologies related to the digestive and intestinal systems.

Tolerability of the first inhaled mannitol dose in children with cystic fibrosis

Tolerability of the first inhaled mannitol dose in children with cystic fibrosis

Serial Assessment of Hemodynamic and Cerebrovascular Changes After Administration of Mannitol in Postoperative Neurosurgical Patients in the Intensive Care Unit: A Combined Transthoracic and Transcranial Color Doppler Study.

Mannitol is widely used in neurosurgical units to mitigate raised intracranial pressure and cerebral edema, crucial in postoperative management. Its hyperosmolar properties reduce brain extracellular fluid, thereby altering cerebral perfusion and cardiac dynamics. However, the temporal and combined effects of mannitol on cardiovascular and cerebrovascular parameters remain inadequately explored in postoperative settings. This prospective observational study enrolled 20 adult patients who underwent elective craniotomies for tumor excision. Mannitol was administered to the patients at a dose of 0.5 mg/kg/dose as a bolus dose over 20 to 30 minutes. The time interval was eight hours between the doses (scheduled dosing). Patients received their first dose of mannitol in the ICU after eight hours of intraoperative dose. The patients were given mannitol for two postoperative days and followed up for two days in the postoperative period. Transthoracic echocardiography and transcranial color Doppler were used to assess cardiovascular and cerebrovascular parameters at multiple intervals post-mannitol administration. Significant increases in mean flow velocities were observed bilaterally immediately post-mannitol administration on the first postoperative day, indicative of improved cerebral blood flow. However, these changes were transient, with no significant variations noted on the second postoperative day. Cerebrovascular resistance, as measured by the pulsatility index, showed non-significant changes bilaterally across both days. Cardiovascular parameters, including stroke volume and cardiac output, remained stable throughout the study period. Mannitol administration at 0.5 g/kg in postoperative neurosurgical patients transiently improves cerebral perfusion without causing significant hemodynamic instability. This study underscores the importance of monitoring both cerebrovascular and cardiovascular parameters post-mannitol administration to optimize patient management and outcomes.

A 30-year perspective of low-dose dexamethasone, a single dose of mannitol and antiseizures prophylaxis on the prognosis of pneumococcal meningitis

Objectives This study details the accumulated experience of more than 31 years using a low-dose systematic dexamethasone protocol with mannitol and antiseizure prophylaxis for the treatment of suspected pneumococcal meningitis. Methods Data have been prospectively collected for the period1977–2018. From 1987, patients with suspected pneumococcal meningitis received 12 mg dexamethasone followed by 4 mg/6 h for 48 h, started before or with the first antibiotic dose. They also received (1) a single intravenous dose of 0.5–1 g/Kg mannitol, and (2) antiseizure prophylaxis with phenytoin. Results In total, 363 episodes of pneumococcal meningitis were recorded. Of these, 242 were treated with the dexamethasone protocol after 1987 and 121 were treated without the protocol. Overall mortality was 11.6% (28/242) among patients treated with dexamethasone and 35% (43/121) among those treated without dexamethasone (p = 0.000). Early mortality was significantly lower at 5.8% (14/242) with dexamethasone and 24% (29/121) without dexamethasone (p = 0.000). Finally, neurological mortality was significantly lower at 7.4% (18/242) with dexamethasone and 23% (28/121) without dexamethasone (p = 0.000). Conclusions A low dose of dexamethasone along with a single dose of mannitol and antiseizures prophylaxis might be useful for reducing both overall and early mortality in pneumococcal meningitis in adult patients.

Efficient production of R-2-(4-hydroxyphenoxy) propionic acid by Beauveria bassiana using biofilm-based two-stage fermentation

In this work, a novel biofilm-based fermentation of Beauveria bassiana was employed to convert R-2- phenoxypropionic acid (R-PPA) to R-2-(4-hydroxyphenoxy) propionic acid (R-HPPA). The biofilm culture model of Beauveria bassiana produced a significantly higher R-HPPA titer than the traditional submerged fermentation method. Mannitol dosage, tryptone dosage, and initial pH were the factors that played a significant role in biofilm formation and R-HPPA synthesis. Under the optimal conditions, the maximum R-HPPA titer and productivity approached 22.2 g/L and 3.2 g/(L·d), respectively. A two-stage bioreactor combining agitation and static incubation was developed to further increase R-HPPA production. The process was optimized to achieve 100 % conversion of R-PPA, with a maximum R-HPPA titer of 50 g/L and productivity of 3.8 g/(L·d). This newly developed biofilm-based two-stage fermentation process provides a promising strategy for the industrial production of R-HPPA and related hydroxylated aromatic compounds.

Comparison of two minimally invasive surgical approaches for hypertensive intracerebral hemorrhage: a study based on postoperative intracranial pressure parameters

BackgroundIncreased intracranial pressure (ICP) in patients with hypertensive intracerebral hemorrhage (HICH) has been associated with poor prognosis. The transsylvian insular approach (TIA) and the transcortical (TCA) approach are applied for patients with HICH. We aimed to compare the postoperative ICP parameters of TIA and TCA to identify which procedure yields better short-term outcomes in patients with basal ganglia hematoma volumes ranging from 30 to 50 mL.MethodsEighty patients with basal ganglia hematomas 30–50 mL were enrolled in this study. Patients were implanted with ICP probes and divided into TIA and TCA groups according to the procedure. The ICP values were continuously recorded for five days at four-hour intervals. Short-term outcomes were evaluated using the length of hospitalization and postoperative consciousness recovery time.ResultsNo statistically significant differences were found in age, sex, GCS score at admission, hematoma volume, and hematoma clearance rate (p > 0.05). The results showed that postoperative initial ICP, ICP on the first postoperative day, mean ICP, DICP20 mmHg × 4 h, postoperative consciousness recovery time, the length of hospitalization, mannitol utilization rate and the mannitol dosage were lower in the TIA group than in the TCA group (p < 0.05). Postoperative consciousness recovery time was positively correlated with ICP on the first postoperative day, and the length of hospitalization was positively correlated with mean ICP.ConclusionsTIA is more effective than TCA in improving the short-term outcomes of patients with basal ganglia hematoma volumes ranging from 30 to 50 mL according to comparisons of postoperative ICP parameters.

Hydration Methods for Cisplatin Containing Chemotherapy: A Systematic Review.

Cisplatin-induced nephrotoxicity (CIN) can be prevented by fluid hydration, electrolyte supplementation, or forced diuresis; however, the best way to prevent CIN is still unknown. The aim of this study was to provide objective evidence on the optimal design of hydration schemes to prevent CIN based on an update of the literature. A Pubmed and Embase search were conducted in December 2021 and repeated in April 2022 and March 2023. Two independent reviewers screened the articles. The included articles were categorized and reviewed per category. Twenty-seven articles met the inclusion criteria. The included studies varied widely. Four out of seven studies investigating diuretics found a protective effect of adding mannitol to the hydration scheme. All six studies investigating duration and amount of volume of hydration found that a short-hydration scheme resulted in less CIN than a longer hydration scheme. Seven out of nine articles evaluating the role of electrolytes found that magnesium supplementation reduced the risk of nephrotoxicity. Three studies investigated the safety of oral hydration and concluded that nephrotoxicity did not occur more frequently after oral hydration. The hydration scheme of cisplatin should be short and consist of a relatively small amount of volume. The scheme should include mannitol and magnesium supplementation. Head-to-head studies are needed to investigate the safety of furosemide compared with mannitol and the dose of mannitol and magnesium.

Development and Validation of a Clinical Prediction Model for Venous Thromboembolism Following Neurosurgery: A 6-Year, Multicenter, Retrospective and Prospective Diagnostic Cohort Study.

Based on the literature and data on its clinical trials, the incidence of venous thromboembolism (VTE) in patients undergoing neurosurgery has been 3.0%~26%. We used advanced machine learning techniques and statistical methods to provide a clinical prediction model for VTE after neurosurgery. All patients (n = 5867) who underwent neurosurgery from the development and retrospective internal validation cohorts were obtained from May 2017 to April 2022 at the Department of Neurosurgery at the Sanbo Brain Hospital. The clinical and biomarker variables were divided into pre-, intra-, and postoperative. A univariate logistic regression (LR) was applied to explore the 67 candidate predictors with VTE. We used a multivariable logistic regression (MLR) to select all significant MLR variables of MLR to build the clinical risk prediction model. We used a random forest to calculate the importance of significant variables of MLR. In addition, we conducted prospective internal (n = 490) and external validation (n = 2301) for the model. Eight variables were selected for inclusion in the final clinical prediction model: D-dimer before surgery, activated partial thromboplastin time before neurosurgery, age, craniopharyngioma, duration of operation, disturbance of consciousness on the second day after surgery and high dose of mannitol, and highest D-dimer within 72 h after surgery. The area under the curve (AUC) values for the development, retrospective internal validation, and prospective internal validation cohorts were 0.78, 0.77, and 0.79, respectively. The external validation set had the highest AUC value of 0.85. This validated clinical prediction model, including eight clinical factors and biomarkers, predicted the risk of VTE following neurosurgery. Looking forward to further research exploring the standardization of clinical decision-making for primary VTE prevention based on this model.

Application Effect of Continuous Lumbar Cistern Fluid Drainage Combined With Decompressive Craniectomy in the Treatment of Severe Craniocerebral Injury

To analyze the application effect of continuous lumbar cistern fluid drainage combined with decompressive craniectomy in the treatment of severe craniocerebral injury. A total of 87 patients with severe craniocerebral injury admitted to our hospital between March 2016 and March 2021 were retrospectively enrolled. They were divided into two groups according to the decompression methods applied, with 42 patients who received standard decompressive craniectomy assigned to the control group and 45 patients who received continuous lumbar cistern fluid drainage combined with standard decompressive craniectomy assigned to the observation group. The primary indicators that were monitored and compared between the two group included the amount of time for patient CT imaging to be clear of subarachnoid hemorrhage, the length-of-stay, the duration of post-operative intubation, the mannitol dose, scores for Glasgow Coma Scale (GCS), prognosis, the incidence of cerebral edema and cerebral infarction, and complications. The secondary indicators that were monitored and compared included intracranial pressure, cerebrospinal fluid antinucleosome protein SP100, and red blood cell count of the two groups before treatment and after continuous drainage for 7 days. The amount of time for CT imaging to be clear of subarachnoid hemorrhage and the length-of-stay of the observation group were shorter than those of the control group, the mannitol dose of the observation group was lower than that of the control group, the incidence of cerebral edema and the incidence of complications of the observation group were lower than those of the control group, and the rate of patients with good prognosis in the observation group was higher than that in the control group ( P<0.05). There was no significant difference in the rate of poor prognosis or mortality between the two groups ( P>0.05). The duration of postoperative intubation of the observation group was (8.24±1.09) d, while that of the control group was (9.22±1.26) d, and the difference between the two groups was statistically significant ( t=3.887, P<0.05). There were 2 cases (4.44%) of cerebral infarction in the observation group, with the infarct volume being (8.36±1.87) cm 3, while there were 9 cases (21.43%) of cerebral infarction in the control group, with the infarct volume being (8.36±1.87) cm 3, and there were statistically significant differences in the incidence and volume of cerebral infarction between the two groups ( χ 2=5.674, t=9.609, P<0.05). After treatment, the intracranial pressure and red blood cell count decreased in both groups and the intracranial pressure, cerebrospinal fluid SP100, and red blood cell count of the observation group were significantly lower than those of the control group ( P<0.05). The cerebrospinal fluid SP100 of the observation group decreased after treatment in comparison with the level before treatment ( P<0.05), while the pre- and post-treatment levels of the control group did not demonstrate any significant difference. Continuous lumbar cistern fluid drainage in patients with severe craniocerebral injury effectively shortens the time required for the body to recover, significantly reduces the level of intracranial pressure, improves the levels of cerebral edema and cerebral infarction, and has a high degree of safety for prognosis and recovery.

Mannitol Challenge to Assess Therapy Response in Asthmatic Children: An Interventional Cohort Study.

Bronchial provocation tests, such as the mannitol challenge, can be performed to identify and quantify the severity of bronchial hyperresponsiveness in asthmatic patients. Studies of the mannitol challenge as a monitoring tool in asthmatic children are limited. Our primary aim was to compare the bronchial hyperresponsiveness to mannitol in treatment-naive asthmatic children between baseline and three months after receiving the indicated asthma prophylaxis. Twenty-three asthmatic patients aged 4-16 years were analyzed in this prospective cohort study. All subjects underwent the mannitol challenge at baseline and after three months of treatment with budesonide ± formoterol. The difference in the provocative dose of mannitol to induce a 15% drop in FEV1 (PD15) between baseline and follow-up, as well as its association with the presence of exercise-induced or nocturnal asthma symptoms, were evaluated. The PD15 value increased significantly post-treatment (228.5 mg [4.50-458.15]; p = 0.04). Independently of the evaluation time point, the PD15 values were significantly lower in the presence of nocturnal asthma symptoms (490 mg [122-635] vs. 635 mg [635-635]; p = 0.03), whereas there was no association between the PD15 value and the presence of exercise-induced asthma (p = 0.73). These results suggest that bronchial hyperresponsiveness to mannitol may be a potential monitoring tool in the pediatric asthmatic population, reflecting therapy response in children receiving prophylactic treatment.

Low dose mannitol versus high dose mannitol to achieve brain relaxation in brain tumor surgery: a meta-analysis

Background: Brain edema is one of the common intraoperative problems in neurosurgery. Brain edema is usually treated by administering a hypertonic solution such as mannitol. Some studies mentioned the use of high-dose mannitol (&gt; 1 g/kg), but it is important to note that mannitol has several drawbacks. This meta-analysis aims to identify the most effective mannitol dose to reduce intraoperative brain edema among brain tumor cases. Methods: We searched for all randomized-controlled trials (RCTs) published in English, which compared various doses of mannitol for brain tumors published between 2010 - 2020. The studies should include adult patients with intracranial tumors who received mannitol to reduce brain edema before opening the dura mater. The primary and secondary outcomes are satisfactory brain relaxation and the need for additional treatment to achieve adequate relaxation, respectively. Result: Three RCTs were identified using an agreed-upon search strategy. A total of 354 patients were included in the meta-analysis. Satisfactory brain relaxation occurred in 70 of 152 and 154 of 202 patients who received low-dose and high-dose mannitol, respectively (RR 0.64 (95% CI, 0.48 – 0.86, p=0.003). There were 59 of 152 and 71 of 202 patients who needed additional treatment to make the brain adequately relax (RR 1.33, 95 % CI 0.97 – 1.83, p=0.08). Conclusion: A mannitol dose of ≥ 1g/kg achieves better brain relaxation. And it required fewer additional measures to relax the brain. These conclusions are drawn from low-quality evidence. Further research on the safety of high-dose mannitol is warranted to ensure its benefit outweighs its harm.

The Titrated Mannitol Improved Central [99mTc] Tc TRODAT-1 Uptake in an Animal Model-A Clinically Feasible Application.

[99mTc]Tc TRODAT-1 is a widely used single photon emission tomography (SPECT) radiopharmaceutical in Asian practice for early detection of central dopaminergic disorders. However, its imaging quality remains sub-optimal. To overcome this problem, mannitol, an osmotic agent was used to observe its effect on improving striatal [99mTc]Tc TRODAT-1 uptake in rat brain by titrated human dosages to investigate a clinically feasible way to improve human imaging quality. [99mTc]Tc TRODAT-1 synthesis and quality control were performed as described. Sprague-Dawley rats were used for this study. The animal in vivo nanoSPECT/CT and ex vivo autoradiography were employed to observe and verify the striatal [99mTc]Tc TRODAT-1 uptake in rat brains using clinically equivalent doses (i.e., 0, 1 and 2 mL groups, each n = 5) of mannitol (20% w/v, equivalent to 200 mg/mL) by an intravenous administration. Specific binding ratios (SBRs) were calculated to express the central striatal uptake in different experimental groups. In the NanoSPECT/CT imaging, the highest SBRs of striatal [99mTc]Tc TRODAT-1 were reached at 75-90 min post-injection. The averaged striatal SBRs were 0.85 ± 0.13 (2 mL normal saline, the control group), 0.94 ± 0.26 (1 mL mannitol group) and 1.36 ± 0.12 (2 mL mannitol group, p < 0.01 which were significantly different than the control as well as 1 mL mannitol groups (p < 0.05). The SBRs from ex vivo autoradiography also showed a comparable trend of the striatal [99mTc]Tc TRODAT-1 uptake in the 2 mL, 1 mL mannitol and the control groups (1.76 ± 0.52, 0.91 ± 0.29, and 0.21 ± 0.03, respectively, p < 0.05). No remarkable changes of vital signs were found in the mannitol groups and the controls. Pre-treated mannitol revealed a significant increase of the central striatal [99mTc]Tc TRODAT-1 uptake in a rat model which not only enabled us to perform pre-clinical studies of dopaminergic related disorders but also provided a potential way to further optimize image quality in clinical practice.

Effect of intravenous administration of 20% Mannitol on optic nerve sheath diameter in patients with raised intracranial pressure

Background and aims: Mannitol is commonly used to reduce elevated intracranial pressure (ICP) in patients with traumatic brain injury, intracranial hemorrhage and acute cerebrovascular accident. Optic nerve sheath diameter (ONSD) has high sensitivity and specificity in diagnosing raised ICP. This study aims to evaluate effect of Mannitol on ONSD in patients with raised ICP.&#x0D; Methods: This was a prospective cohort observational study of adult patients receiving osmotherapy for increased ICP admitted to the ICU. Baseline ONSD (T1) was recorded bilaterally followed by administration of Mannitol. ONSD was remeasured bilaterally at 30 (T2), 60 (T3) and 120 (T4) minutes after completion of administration of mannitol. Peak inspiratory pressures and PEEP were recorded for patients on mechanical ventilation.&#x0D; Results: Of the 40 patients included in the study, the mean age of patients was 54.03 ±19.15 years. Among them 26 were mechanically ventilated. Compared to the baseline values of 6.1 ± 0.74 mm, the mean ONSDs at T2, T3 and T4 were significantly lower after administration of 20% Mannitol with all p values &lt; 0.001. A statistically significant correlation between change in ONSD (ΔONSD) at each time point and the dose of Mannitol administered was observed.&#x0D; Conclusion: ONSD can be used for monitoring effectiveness of osmotherapy on a point-of-care basis in patients with elevated ICP.

Study of changes in cardiac output, stroke volume, and cardiac index with two doses of mannitol infusion during supratentorial craniotomy

BackgroundMannitol is used extensively in supratentorial surgeries to reduce intracranial pressure. The optimum dose of mannitol is still a matter of debate. We have done this prospective, comparative and randomized study to compare the changes in cardiac output (CO), stroke volume (SV), cardiac index (CI), central venous pressure (CVP), brain relaxation, and side effects in two doses of mannitol infusion. We have divided 60 enrolled patients randomly into two groups. We infused 0.7gm kg-1, 20% mannitol in 20 min duration in Group A and 1.4gm kg-1 of 20% mannitol in 20 min in Group B. Flotrac transducer was connected to assess SV, CO, and CI. We recorded and analyzed brain relaxation score, HR, MAP, CVP, SV, CO, and CI at predefined time intervals after mannitol infusion. Chi-square test and unpaired t test were used to analyze categorical and continuous variables between two groups.ResultsWe have found statistically significant and better brain relaxation in Group B than Group A. Significant (p<0.05) difference in CVP was found between the groups at 10, 20 min after start of infusion, and 5, 10, and 15 min after termination of infusion. We found significant (p<0.05) difference in SV, CO, and CI between the groups at most of the time periods.ConclusionsWe can conclude that higher dose of mannitol provides better brain relaxation intraoperatively without significant adverse effects. We assessed more changes in hemodynamic and cardiac parameters with higher dose of mannitol that did not cause clinical deterioration.

Label-Free Assessment of Mannitol Accumulation Following Osmotic Blood-Brain Barrier Opening Using Chemical Exchange Saturation Transfer Magnetic Resonance Imaging.

Mannitol is a hyperosmolar agent for reducing intracranial pressure and inducing osmotic blood-brain barrier opening (OBBBO). There is a great clinical need for a non-invasive method to optimize the safety of mannitol dosing. The aim of this study was to develop a label-free Chemical Exchange Saturation Transfer (CEST)-based MRI approach for detecting intracranial accumulation of mannitol following OBBBO. In vitro MRI was conducted to measure the CEST properties of D-mannitol of different concentrations and pH. In vivo MRI and MRS measurements were conducted on Sprague-Dawley rats using a Biospec 11.7T horizontal MRI scanner. Rats were catheterized at the internal carotid artery (ICA) and randomly grouped to receive either 1 mL or 3 mL D-mannitol. CEST MR images were acquired before and at 20 min after the infusion. In vitro MRI showed that mannitol has a strong, broad CEST contrast at around 0.8 ppm with a mM CEST MRI detectability. In vivo studies showed that CEST MRI could effectively detect mannitol in the brain. The low dose mannitol treatment led to OBBBO but no significant mannitol accumulation, whereas the high dose regimen resulted in both OBBBO and mannitol accumulation. The CEST MRI findings were consistent with 1H-MRS and Gd-enhanced MRI assessments. We demonstrated that CEST MRI can be used for non-invasive, label-free detection of mannitol accumulation in the brain following BBBO treatment. This method may be useful as a rapid imaging tool to optimize the dosing of mannitol-based OBBBO and improve its safety and efficacy.

Eosinophil depletion with benralizumab is associated with attenuated mannitol airway hyperresponsiveness in severe uncontrolled eosinophilic asthma

Airway hyperresponsiveness (AHR) and eosinophilia are hallmarks of persistent asthma. We investigated whether eosinophil depletion with benralizumab might attenuate indirect mannitol AHR in severe uncontrolled asthma using a pragmatic open-label design. After a 4-week run-in period with provision of usual inhaled corticosteroids and/or long-acting β-agonist (baseline), adults with mannitol-responsive uncontrolled severe eosinophilic asthma received 3 doses of open-label benralizumab 30 mg every 4 weeks, followed by 16 weeks' washout after the last dose. The primary outcome was doubling difference (DD) in provocative dose of mannitol required to decrease FEV1 by 10% (PD10) at the end point after 12 weeks, powered at 90% with 18 patients required to detect 1 DD. Secondary outcomes included measures assessed by the asthma control questionnaire and mini-asthma quality of life questionnaire. Twenty-one patients completed 12 weeks' benralizumab therapy at the end point at week 12. Mean (SEM) age was 53 (4) years, and FEV1 80.2% (4.1%) inhaled corticosteroid dose was 1895 (59) μg, with 12 receiving long-acting muscarinic antagonist and 13 leukotriene receptor antagonists. Improvement in AHR was significant by 8 weeks, with a mean 2.1 DD (95% confidence interval 1.0, 3.3; P< .01) change in PD10 at week 12, while mean changes in asthma control questionnaire and mini-asthma quality of life questionnaire were significant by week 2 and sustained over 12 weeks, both exceeding the minimal important difference. Peripheral blood eosinophils were depleted by 2 weeks (439 to 6 cells/μL). No significant improvement occurred in lung function after 12 weeks. Domiciliary peak flow and symptoms also improved with benralizumab. Eosinophil depletion results in clinically meaningful attenuated AHR in severe uncontrolled asthma patients.

Manipulating the blood labyrinth barrier with mannitol to prevent cisplatin-induced hearing loss

Cisplatin, a chemotherapeutic medication, remains in the cochlea indefinitely, causing permanent hearing loss. Mannitol, a diuretic medication, has been shown to increase the permeability of the blood labyrinth barrier (BLB). We hypothesize that mannitol increases the permeability of the BLB and therefore increases the rate of entry and egression of cisplatin and entry of otoprotective agents. Rats treated with cisplatin (t = 0) were given mannitol at either t = 0, t = 6 or t = 0,6 h. Another group of rats were treated with cisplatin with mannitol at 0 h and NAC/STS with and without mannitol at 6 h. Concurrent mannitol (t = 0) transiently increased cisplatin entry into the inner ear and exacerbated cisplatin-induced hearing loss. Delayed mannitol (t = 6) did not significantly increase cisplatin entry into the inner ear and preserved inner ear functionality and structure. Additional-delayed mannitol (t = 0,6) showed that the 2nd dose of mannitol prevented exacerbation of cisplatin with mannitol-induced hearing loss. A combination of delayed NAC/STS with mannitol (t = 6) was better than NAC/STS (t = 6) alone at providing partial to full protection against cisplatin with mannitol-induced hearing loss. In conclusion, mannitol injections at t = 6 h reduced cisplatin ototoxicity (instead of exacerbating cisplatin ototoxicity at t = 0 h), and it enhanced the otoprotective efficacy of antioxidants. This may provide an important therapeutic strategy to prevent cisplatin-induced hearing loss, a direct implication in protection against hearing loss in cisplatin chemotherapy.

Volume replacement is associated with a diminished osmolar effect of mannitol in patients with acute brain injury

IntroductionAnimal experiments recently demonstrated that replacing urinary loses with crystalloid diminishes the therapeutic effect of mannitol by reducing the increase in osmolality. We aimed to investigate whether this effect is similarly seen in in brain-injured patients by studying the association between total body fluid balance (TBB) and the osmolar response to mannitol. MethodsWe performed a retrospective cohort study of adult patients with acute brain injury between 2015 and 2021 who received ≥ 2 doses of mannitol within 8 hours and no intercurrent concentrated saline solution. We analyzed the association between the change in TBB (∆TBB) and change in osmolality (∆Osm) before and after mannitol in a linear model, both as univariate and after adjustment for common confounding factors. ResultsOf 6,145 patients who received mannitol, 155 patients met inclusion criteria (mean age 60 ± 17 years, 48% male, 83% white). The mean total mannitol dose was 2 ± 0.5 g/kg and the mean change in plasma osmolality was 7.9 ± 7.1 mOsm/kg. Each 1 L increase in ∆TBB was associated with a change of -1.1 mOsm/L in ∆Osm (95% CI [-2.2, -0.02], p = 0.045). The magnitude of association was similar to that of total mannitol dose and remained consistent in an adjusted model and after excluding outliers. ConclusionsIn patients with acute brain injury, a positive TBB is associated with a diminished mannitol-induced increase in plasma osmolality. Future prospective studies are needed to confirm these findings and their influence on the therapeutic effect of mannitol.