The use of the mannitol test as an outcome measure in asthma intervention studies: a review and practical recommendations.

BACKGROUND: The mannitol test is an indirect bronchial challenge test widely used in diagnosing asthma. Response to the mannitol test correlates with the level of eosinophilic and mast cell airway inflammation, and a positive mannitol test is highly predictive of a response to anti-inflammatory treatment with inhaled corticosteroids. The response to mannitol is a physiological biomarker that may, therefore, be used to assess the response to other anti-inflammatory treatments and may be of particular interest in early phase studies that require surrogate markers to predict a clinical response. The main objectives of this review were to assess the practical aspects of using mannitol as an endpoint in clinical trials and provide the clinical researcher and respiratory physician with recommendations when designing early clinical trials. METHODS: The aim of this review was to summarise previous uses of the mannitol test as an outcome measure in clinical intervention studies. The PubMed database was searched using a combination of MeSH and keywords. Eligible studies included intervention or repeatability studies using the standard mannitol test, at multiple timepoints, reporting the use of PD15 as a measure, and published in English. RESULTS: Of the 193 papers identified, 12 studies met the inclusion criteria and data from these are discussed in detail. Data on the mode of action, correlation with airway inflammation, its diagnostic properties, and repeatability have been summarised, and suggestions for the reporting of test results provided. Worked examples of power calculations for dimensioning study populations are presented for different types of study designs. Finally, interpretation and reporting of the change in the response to the mannitol test are discussed. CONCLUSIONS: The mechanistic and practical features of the mannitol test make it a useful marker of disease, not only in clinical diagnoses, but also as an outcome measure in intervention trials. Measuring airway hyperresponsiveness to mannitol provides a novel and reproducible test for assessing efficacy in intervention trials, and importantly, utilises a test that links directly to underlying drivers of disease.

Delayed transient obstructive hydrocephalus after cerebral aneurysm rupture: A case report.

RATIONALE: Obstructive hydrocephalus (OH) frequently occurs in patients with a ruptured cerebral aneurysm (CA), and it may lead to severe neurological deficits, including life-threatening brain herniation. OH generally occurs in the early stage of CA rupture, rather than in the late stage, and rarely resolves without therapy. PATIENT CONCERNS: A 64-year-old woman with a ruptured anterior communicating artery aneurysm was treated with coil embolization. Nineteen days after her CA rupture, because of the delayed transient OH, she experienced a dramatic cycle in consciousness over 9 hours: wakefulness-drowsiness-coma-drowsiness-wakefulness. DIAGNOSIS: The patient was diagnosed with delayed transient obstructive hydrocephalus, which is a very rare condition. INTERVENTIONS: Mannitol was administered to reduce intracranial pressure. OUTCOMES: The patient was discharged from the hospital 30 days after admission, with a final GCS score of 15 and without weaknesses. At follow-up 2 months after discharge, brain CT revealed non-recurrence of hydrocephalus. LESSONS: A blood clot of any size in the ventricle is likely to lead to obstructive hydrocephalus. Prolonged bed rest for IVH patients may help to reduce the incidence of delayed OH.

Delayed pneumocephalus induced by repeated percutaneous aspiration after spinal surgery: A case report and literature review.

RATIONALE: Severe tension pneumocephalus can lead to drowsiness, coma, and even brain hernia and death. The occurrence of delayed pneumocephalus after spinal surgery is rarely reported and often ignored. Herein, we report a case of delayed pneumocephalus after repeated percutaneous aspiration following spinal surgery. PATIENT CONCERNS: A 55-year-old man was admitted in October 2020 because of aggravation in bilateral lower limb weakness and dysuria for seven days. He was diagnosed with liver cancer a year ago, and he underwent several operations because of tumor recurrence. The patient underwent thoracic vertebrae tumor excision on this admission, and no cerebrospinal fluid leakage was discovered during surgery. After the third drainage by percutaneous aspiration, the patient complained of severe headache and vomiting on postoperative day 16. DIAGNOSIS: Emergency brain computed tomography revealed massive pneumocephalus. INTERVENTIONS: Thereafter, suction drainage was discontinued, and he was placed on bed rest and administered intravenous mannitol. OUTCOMES: Repeated computed tomography showed complete resolution of the pneumocephalus after five days. LESSONS: Wound exudates and cystic fluid after spinal surgery should be differentiated from cerebrospinal fluid leakage. Reckless percutaneous aspirations can form pneumocephalus in patients with an occult dural injury, and pneumocephalus can occur up to 16 days after surgery. Early diagnosis of pneumocephalus is crucial to avoid severe consequences.

Hyperosmolarity stimulates transporter-mediated insertion of estrone sulfate into the plasma membrane, but inhibits the uptake by SLC10A1 (NTCP).

Many drugs are largely hydrophobic molecules; a transporter might conceivably insert these into the plasma membrane. At least 18 transporters from diverse families have been reported to transport the model compound estrone sulfate alias estrone-3-sulfate (E3S). Out of these, we recently examined SLC22A11 (OAT4). We concluded from a comparison of E3S and uric acid transport that SLC22A11 does not translocate E3S into the cytosol, but into the plasma membrane. Here we present a hyperosmolarity alias hypertonicity assay to differentiate transport mechanisms. Human transporters were expressed heterologously in 293 cells. Solute uptake into intact cells was measured by LC-MS. Addition of mannitol or sucrose led to rapid cell shrinkage, but cell viability after 60 min in hyperosmolar buffer was not impaired. A decrease in substrate accumulation with increasing osmolarity as observed here for several substrates and the transporters SLC22A11, ETT (SLC22A4), OCT2 (SLC22A2), OAT3 (SLC22A8), and MATE1 (SLC47A1) suggests regular substrate translocation into the cytosol. An increase as observed for E3S transport by SLC22A11, OAT3, MATE1, SLC22A9, and SLC10A6 implies insertion into the membrane. In marked contrast to the other E3S transporters, the bile acid transporter SLC10A1 (NTCP, Na+ taurocholate co-transporting polypeptide) showed a decrease in the accumulation of E3S in hyperosmolar buffer; the same was observed with taurocholic acid. Indeed, our data from several functional assays strongly suggest that the transport mechanism is identical for both substrates. Apparently, a unique transport mechanism has been established for SLC10A1 by evolution that ensures the transport of amphipathic, detergent-like molecules into the cytosol.

Comparison of equiosmolar doses of 10% hypertonic saline and 20% mannitol for controlling intracranial hypertention in patients with large hemispheric infarction.

OBJECTIVE: We conducted this prospective self-crossover controlled trial to compare the efficacy and safety of 10 % hypertonic saline (HS) and 20 % mannitol in doses of similar osmotic burden for the treatment of increased intracranial pressure (ICP) in patients with large hemispheric infarction (LHI). PATIENTS AND METHODS: Patients with LHI were enrolled from January 2017 to January 2018. We used an alternating treatment protocol to compare the effects of HS with mannitol given for episodes of increased ICP in patients with LHI. Indicators such as ICP, mean arterial pressure (MAP) and cerebral perfusion pressure (CPP) were continuously monitored at regular intervals for 240 min after initiation of infusion. Electrolytes, plasma osmolality and renal functions were measured before and 240 min after initiation of infusion to compare the efficacy and safety of the two drugs. RESULTS: A total of 49 episodes of increased ICP occurred in 14 patients with LHI, of which 24 were infused with 10 % HS and 25 with 20 % mannitol. Both the treatments were equally effective in reducing ICP (P < 0.01). The differences in the duration and degree of reduction were not significant between the groups (P > 0.05). Although both the osmolar agents decreased MAP, the degree was greater in the mannitol group (P < 0.05) at T120. The increase in CPP was greater in the HS group compared with the mannitol group (P < 0.05) at T120. However, HS was associated with faster heart rate (HR) and higher serum chloride levels (P < 0.05). Changes in serum sodium levels and osmolality were not significant between the groups in spite of being higher in the HS group. CONCLUSIONS: Both the drugs can serve as first-line agents for treating intracranial hypertension caused by LHI and should be selected rationally according to the differences in efficacy and adverse effects.

Comparative efficacy and safety of glycerol versus mannitol in patients with cerebral oedema and elevated intracranial pressure: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Glycerol is thought to be superior to mannitol in the treatment of cerebral oedema and elevated intracranial pressure (ICP), particularly with safety concerns. However, the current evidence remains insufficient. Therefore, we aimed to compare the efficacy and safety of glycerol versus mannitol in this meta-analysis. METHODS: PubMed, EMBASE, Web of Science, CENTRAL, China National Knowledge Infrastructure, Wanfang Database, Chongqing VIP information, ClinicalTrials.gov, and the reference lists of relevant articles were searched for randomized controlled trials comparing glycerol and mannitol in patients with brain oedema and elevated ICP. Two investigators independently identified the articles, assessed the study quality and extracted data. Data analyses were performed using RevMan software. RESULTS AND DISCUSSION: Thirty trials involving 3144 patients met our inclusion criteria. Pooled data indicated that glycerol and mannitol had comparable effectiveness in controlling cerebral oedema (RR, 1.00; 95% CI, 0.97 to 1.03; p = .97), but the risks of acute kidney injury and electrolyte disturbances were significantly lower with glycerol (RR, 0.21; 95% CI, 0.16 to 0.27 and RR, 0.23; 95% CI, 0.17 to 0.30, respectively) than mannitol. Moreover, there seemed to be a lower probability of rebound ICP after the withdrawal of glycerol. Neither haemolysis nor elevated blood glucose levels were observed in the glycerol group. WHAT IS NEW AND CONCLUSION: Regarding the balance between efficacy and safety, glycerol could be an effective and more tolerable alternative therapy for cerebral oedema and elevated ICP than mannitol, especially for high-risk populations of renal failure.

Equimolar doses of hypertonic agents (saline or mannitol) in the treatment of intracranial hypertension after severe traumatic brain injury.

BACKGROUND: Mannitol and hypertonic saline (HTS) are effective in reducing intracranial pressure (ICP) after severe traumatic brain injury (TBI). However, their efficacy on the ICP has not been evaluated rigorously. OBJECTIVE: To evaluate the efficacy of repeated bolus dosing of HTS and mannitol in similar osmotic burdens to treat intracranial hypertension (ICH) in patients with severe TBI. METHODS: The authors used an alternating treatment protocol to evaluate the efficacy of HTS with that of mannitol given for ICH episodes in patients treated for severe TBI at their hospital during 2017 to 2019. Doses of similar osmotic burdens (20% mannitol, 2 ml/kg, or 10% HTS, 0.63 ml/kg, administered as a bolus via a central venous catheter, infused over 15 minutes) were given alternately to the individual patient with severe TBI during ICH episodes. The choice of osmotic agents for the treatment of the initial ICH episode was determined on a randomized basis; osmotic agents were alternated for every subsequent ICH episode in each individual patient. intracranial pressure (ICP), mean arterial pressure (MAP), and cerebral perfusion pressure (CPP) were continuously monitored between the beginning of each osmotherapy and the return of ICP to 20 mm Hg. The duration of the effect of ICP reduction (between the beginning of osmotherapy and the return of ICP to 20 mm Hg), the maximum reduction of ICP and its time was recorded after each dose. Serum sodium and plasma osmolality were measured before, 0.5 hours and 3 hours after each dose. Adverse effects such as central pontine myelinolysis (CPM), severe fluctuations of serum sodium and plasma osmolality were assessed to evaluate the safety of repeated dosing of HTS and mannitol. RESULTS: Eighty three patients with severe TBI were assessed, including 437 ICH episodes, receiving 236 doses of HTS and 221 doses of mannitol totally. There was no significant difference between equimolar HTS and mannitol boluses on the magnitude of ICP reduction, the duration of effect, and the time to lowest ICP achieved (P > .05). The proportion of efficacious boluses was higher for HTS than for mannitol (P = .016), as was the increase in serum sodium (P = .038). The serum osmolality increased immediately after osmotherapy with a significant difference (P = .017). No cases of CPM were detected. CONCLUSION: Repeat bolus dosing of 10% HTS and 20% mannitol appears to be significantly and similarly effective for treating ICH in patients with severe TBI. The proportion of efficacious doses of HTS on ICP reduction may be higher than mannitol.

Hypertonic Saline is Superior to Mannitol for the Combined Effect on Intracranial Pressure and Cerebral Perfusion Pressure Burdens in Patients With Severe Traumatic Brain Injury.

BACKGROUND: Hypertonic saline (HTS) and mannitol are effective in reducing intracranial pressure (ICP) after severe traumatic brain injury (TBI). However, their simultaneous effect on the cerebral perfusion pressure (CPP) and ICP has not been studied rigorously. OBJECTIVE: To determine the difference in effects of HTS and mannitol on the combined burden of high ICP and low CPP in patients with severe TBI. METHODS: We performed a case-control study using prospectively collected data from the New York State TBI-trac® database (Brain Trauma Foundation, New York, New York). Patients who received only 1 hyperosmotic agent, either mannitol or HTS for raised ICP, were included. Patients in the 2 groups were matched (1:1 and 1:2) for factors associated with 2-wk mortality: age, Glasgow Coma Scale score, pupillary reactivity, hypotension, abnormal computed tomography scans, and craniotomy. Primary endpoint was the combined burden of ICPhigh (> 25 mm Hg) and CPPlow (< 60 mm Hg). RESULTS: There were 25 matched pairs for 1:1 comparison and 24 HTS patients matched to 48 mannitol patients in 1:2 comparisons. Cumulative median osmolar doses in the 2 groups were similar. In patients treated with HTS compared to mannitol, total number of days (0.6 ± 0.8 vs 2.4 ± 2.3 d, P < .01), percentage of days with (8.8 ± 10.6 vs 28.1 ± 26.9%, P < .01), and the total duration of ICPhigh + CPPlow (11.12 ± 14.11 vs 30.56 ± 31.89 h, P = .01) were significantly lower. These results were replicated in the 1:2 match comparisons. CONCLUSION: HTS bolus therapy appears to be superior to mannitol in reduction of the combined burden of intracranial hypertension and associated hypoperfusion in severe TBI patients.

A pilot study evaluating the effect of mannitol and hypertonic saline solution in the treatment of increased intracranial pressure in 2 cats and 1 dog naturally affected by traumatic brain injury.

OBJECTIVE: To evaluate the effects of iso-osmolar doses of 18% mannitol and 3% sodium chloride (NaCl) solutions in decreasing intracranial pressure (ICP) in animals with severe traumatic brain injury (TBI). DESIGN: Prospective uncontrolled interventional study. SETTING: Veterinary university teaching hospital. ANIMALS: Two cats and 1 dog with TBI with a modified Glasgow Coma Scale score ≤8 after hemodynamic stabilization, and with brain magnetic resonance imaging changes suggestive of intracranial hypertension. INTERVENTIONS: Animals were surgically instrumented for direct ICP measurement, then randomly treated with iso-osmolar doses of 18% mannitol or 3% NaCl. Direct ICP and cerebral perfusion pressure (CPP) were recorded both before treatment and for 120 minutes following drug administration. MEASUREMENTS AND MAIN RESULTS: Direct ICP and CPP were recorded both before treatment and at 5 additional time points following administration over the subsequent 120 minutes. Case 1 received 3% NaCl without any response to therapy; refractory posttraumatic hypertension was suspected. Case 2 was treated with 3% NaCl; ICP decreased by 40.7% and CPP increased by 15%; however, these effects were transient. Case 3 received 18% mannitol, and ICP decreased by 19% and CPP increased to normal. However, there was a rebound increase in ICP that was higher than pretreatment values, and CPP decreased slightly before it gradually increased to normal values towards the end of the study. CONCLUSIONS: Both mannitol and hypertonic saline decrease ICP and improve CPP, but the effect observed in this pilot study suggests that there might be differences in the duration of these effects. Appropriately designed studies in a larger and homogeneous population are warranted to further investigate these findings.

Investigating the Possible Protective Role of Direct Intra-arterial Administration of Mannitol and N-Acetylcysteine and Per Os Administration of Simvastatin Against Contrast-Induced Nephropathy: An Experimental Study in a Rabbit Model.

PURPOSE: Contrast-induced nephropathy (CIN) is one of the leading causes of hospital-acquired acute kidney injury due to the use of iodinated contrast media in various interventional procedures like endovascular aneurysm repair. Its pathophysiology remains mostly unclear. The purpose of the present study was to comparatively study the possible protective role of direct intra-arterial administration of mannitol and acetylcysteine and per os administration of simvastatin in a histopathological level. MATERIALS AND METHODS: In the present study, we administered iopromide directly in the infrarenal aorta of 24 New Zealand white rabbits after laparotomy. Animals were divided in four groups of six: G1 received iopromide with no protection, G2 iopromide with mannitol, G3 iopromide with acetylcysteine, and G4 iopromide with simvastatin. Renal function blood parameters were assessed prior to the administration, and in 48 h; histopathological evaluation of the kidneys was performed. RESULTS: CIN was evident only in the no protection group G1. Moreover, G1 demonstrated significantly more severe lesions than groups G2, G3, and G4 regarding histopathological findings in glomeruli, vacuolization of tubular epithelial cells, tubular proteinaceous casts, and tubular necrosis. According to our results, intra-arterial administration of mannitol seems to be effective in protection against tubular necrosis. CONCLUSION: In general, all three agents demonstrated a protective role in preventing the development of CIN, although it seems that there are various pathways that remain to be investigated further.

Comparison of electrical impedance tomography and intracranial pressure during dehydration treatment of cerebral edema.

Cerebral edema after brain injury can lead to brain damage and death if diagnosis and treatment are delayed. This study investigates the feasibility of employing electrical impedance tomography (EIT) as a non-invasive imaging tool for monitoring the development of cerebral edema, in which impedance imaging of the brain related to brain water content is compared with intracranial pressure (ICP). We enrolled forty patients with cerebral hemorrhage who underwent lateral external ventricular drain with intraventricular ICP and EIT monitoring for 3 h after initiation of dehydration treatment. The average reconstructed impedance value (ARV) calculated from EIT images was compared with ICP. Dehydration effects induced changes in ARV and ICP showed a close negative correlation in all patients, and the mean correlation reached R2 = 0.78 ±â€¯0.16 (p < .001). A regression equation (R2 = 0.62, p < .001) was formulated from the total of measurement data. The 95% limits of agreement were - 6.13 to 6.13 mmHg. Adaptive clustering and variance analysis of normalized changes in ARV and ICP showed 92.5% similarity and no statistically significant differences (p > .05). Moreover, the sensitivity, specificity and area under the curve of changes in ICP >10 mmHg were 0.65, 0.73 and 0.70 respectively. The findings show that EIT can monitor changes in brain water content associated with cerebral edema, which could provide a real-time and non-invasive imaging tool for early identification of cerebral edema and the evaluation of mannitol dehydration.

Hypertonic Mannitol for the Prevention of Intradialytic Hypotension: A Randomized Controlled Trial.

RATIONALE & OBJECTIVE: Intradialytic hypotension (IDH) is a common complication at the initiation of hemodialysis (HD) therapy, is associated with greater mortality, and may be related to relatively rapid shifts in plasma osmolality. This study sought to evaluate the effect of an intervention to minimize intradialytic changes in plasma osmolality on the occurrence of IDH. STUDY DESIGN: Double-blind, single-center, randomized, controlled trial. SETTING & PARTICIPANTS: Individuals requiring initiation of HD for acute or chronic kidney disease. INTERVENTION: Mannitol, 0.25g/kg/h, versus a similar volume of 0.9% saline solution during the first 3 HD sessions. OUTCOMES: The primary end point was average decline in systolic blood pressure (SBP). The secondary end point was the proportion of total sessions complicated by IDH (defined as a decrease ≥ 20mm Hg from the pre-HD SBP). Exploratory end points included biomarkers of cardiac and kidney injury. RESULTS: 52 patients were randomly assigned and contributed to 156 study visits. There were no significant differences in average SBP decline between the mannitol and placebo groups (15±11 vs 19±16mm Hg; P = 0.3). The proportion of total sessions complicated by IDH was lower in the mannitol group compared to placebo (25% vs 43%), with a nominally lower risk for developing an episode of IDH (OR, 0.38; 95% CI, 0.14-1.00), though this finding was of borderline statistical significance (P = 0.05). There were no consistent differences in cardiac and kidney injury biomarker levels between treatment groups. LIMITATIONS: Modest sample size and number of events. CONCLUSIONS: In this pilot randomized controlled trial studying patients requiring initiation of HD, we found no difference in absolute SBP decline between those who received mannitol and those who received saline solution. However, there were fewer overall IDH events and a nominally lower risk for dialysis sessions being complicated by IDH in the mannitol group. A larger multicenter randomized controlled trial is warranted. FUNDING: Government funding to an author (Dr Mc Causland is supported by National Institute of Diabetes and Digestive and Kidney Diseases grant K23DK102511). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01520207.

Mannitol for the Prevention of Peri-Operative Acute Kidney Injury: A Systematic Review.

OBJECTIVE/BACKGROUND: Post-operative acute kidney injury (AKI) is a frequent peri-operative complication that negatively affects morbidity and mortality. Mannitol is frequently used peri-operatively for renal protection, although evidence for its use is ambiguous. A systematic review was conducted to clarify whether there is evidence supporting peri-operative mannitol administration for the prevention of post-operative AKI. METHODS: A systematic literature search was performed in MEDLINE/Pubmed, Embase, the Cochrane Library, Clinical Trials registry, and the Cochrane Central Register of Controlled Trials (CENTRAL). Eligibility criteria were (i) population (studies involving adult patients undergoing surgery or a related intervention); (ii) intervention (intravenous mannitol administered in either the pre- or intra-operative period with comparison to controls); and (iii) predefined outcomes (post-operative AKI or respective renal end points/surrogates). RESULTS: In total, 1,538 articles published between January 1990 and October 2018 were identified. After checking for eligibility, 22 studies, including 17 prospective and/or randomised controlled trials and five retrospective studies, were included. The investigations involved various fields of surgery, such as aortic surgery, cardiac surgery with cardiopulmonary bypass, and urological procedures, including partial nephrectomy. Significant heterogeneity, limited sample size, and mostly short follow up periods were noted. CONCLUSION: Given the available evidence, the peri-operative use of mannitol to prevent AKI cannot be considered an evidence based intervention in cardiac surgery, partial nephrectomy, and/or other major surgery. Further research is required with a focus on patients at high risk of post-operative AKI.

Transcriptome analysis of signaling pathways of human peritoneal mesothelial cells in response to different osmotic agents in a peritoneal dialysis solution.

BACKGROUND: Glucose is a primary osmotic agent in peritoneal dialysis (PD) solutions, but its long-term use causes structural alteration of the peritoneal membrane (PM). Hyperbranched polyglycerol (HPG) is a promising alternative to glucose. This study was designed to compare the cellular responses of human peritoneal mesothelial cells (HPMCs) to these two different osmotic agents in a hypertonic solution using transcriptome analysis. METHODS: Cultured HPMCs were repeatedly exposed to HPG-based or Physioneal 40 (PYS, glucose 2.27%) hypertonic solutions. Transcriptome datasets were produced using Agilent SurePrint G3 Human GE 8 × 60 microarray. Cellular signaling pathways were examined by Ingenuity Pathway Analysis (IPA). Protein expression was examined by flow cytometry analysis and Western blotting. RESULTS: The HPG-containing solution was better tolerated compared with PYS, with less cell death and disruption of cell transcriptome. The levels of cell death in HPG- or PYS- exposed cells were positively correlated with the number of affected transcripts (HPG: 128 at day 3, 0 at day 7; PYS: 1799 at day 3, 212 at day 7). In addition to more affected "biosynthesis" and "cellular stress and death" pathways by PYS, both HPG and PYS commonly affected "sulfate biosynthesis", "unfolded protein response", "apoptosis signaling" and "NRF2-mediated oxidative stress response" pathways at day 3. PYS significantly up-regulated HLA-DMB and MMP12 in a time-dependent manner, and stimulated T cell adhesion to HPMCs. CONCLUSION: The lower cytotoxicity of hypertonic HPG solution is in agreement with its transient and minimal impact on the pathways for the "biosynthesis of cell constituents" and the "cellular stress and death". The significant up-regulation of HLA-DMB and MMP12 by PYS may be part of its initiation of immune response in the PM.

Effect of Mannitol on Intraocular Pressure in Vitrectomized and Nonvitrectomized Eyes: A Prospective Comparative Study.

PURPOSE: To compare the effect of mannitol in reducing intraocular pressure (IOP) in vitrectomized and nonvitrectomized eyes. MATERIALS AND METHODS: Prospective comparative case study. Eyes with IOP≥40 mm Hg were included. Eyes which are vitrectomized and silicon oil filled were classified as group 1, and nonvitrectomized open-angle eyes were classified as group 2. Mannitol (20%, 1 g/kg) was administered intravenously over 30 minutes, and IOP was recorded at 30 minutes interval till 2 hours and at the third and fourth hour from the start of mannitol. RESULTS: Thirty eyes (patients) were recruited in each group. Mean (SD) IOP reduced from 48.5±5.2 to 43.7±8 at 30 minutes, 40.7±8.4 at 60 minutes, 37.3±9.6 at 90 minutes, 35.6±10.4 at 2 hours, 34±10.7 at 3 hours, and 33±11.2 mm Hg at 4 hours in group 1, and from 48.9±6.5 to 43.2±8.6 at 30 minutes, 40.2±7.8 at 60 minutes, 36.7±7.3 at 90 minutes, 35.1±7.7 at 2 hours, 34.2±8.8 at 3 hours, and 35.7±9.4 mm Hg at 4 hours in group 2. There was a significant reduction in IOP at each time point compared with baseline in both the groups (P<0.001). There was no significant difference in IOP between the 2 groups at each time point. CONCLUSION: Mannitol reduces IOP significantly in both vitrectomized and nonvitrectomized eyes.

Phase III Trial of Intravenous Mannitol Versus Placebo During Nephron-sparing Surgery: Post Hoc Analysis of 3-yr Outcomes.

Our recently reported phase III trial demonstrated that patients undergoing nephron-sparing surgery (NSS) with an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73 m2 who received mannitol had no improvement in renal function at 6 mo compared with those who received placebo. Some authors have suggested that benefit is restricted to subgroups, such as those with comorbidities. We assessed whether preoperative eGFR, or other patient and surgical factors modified the effect of mannitol on postoperative outcomes at 6 mo and with extended follow-up. We also assessed whether mannitol was associated with differences in long-term GFR years after surgery. No significant difference between the mannitol or placebo groups (mean eGFR difference: 1.4; 95% confidence interval: -2.6, 5.3; p = 0.5) was found in the 134 patients with known eGFR at 3 yr after NSS. At both 6 mo and 3 yr, the effect of mannitol was not significantly modified by patient or surgical factors including preoperative eGFR. In summary, we validated our original trial conclusions by finding that intraoperative use of mannitol does not improve either short- or long-term renal function in patients undergoing NSS. Specifically, there is no evidence that comorbidities, including lower preoperative eGFR, modify the effect of mannitol. PATIENT SUMMARY: Use of mannitol at the time of partial nephrectomy does not improve either short- or long-term renal function even in patients with comorbidities, including lower preoperative renal function. The routine use of intraoperative mannitol should be discontinued.

Sequential changes in urine production, glomerular filtration rate, and electrolyte excretion after mannitol administration.

INTRODUCTION: Acute kidney injury (AKI) leading to severe uremia is associated with high morbidity and mortality. Mannitol is an osmotic diuretic, widely used in the management of AKI, both as a bolus injection and as a constant rate infusion (CRI). OBJECTIVES: To determine the plasma concentration of mannitol after a bolus injection and CRI at the recommended dosages, and to assess the effect of mannitol on renal function variables including urine production, glomerular filtration rate (GFR), and solute excretion. METHODS: Prospective cross-over design study, using 6 healthy dogs. Each dog underwent 3 protocols with at least a 7-day washout period between protocols. The first protocol included bolus injection of mannitol, the second protocol included bolus injection followed by CRI of mannitol and the third protocol (control) included injection of 5% dextrose in water (D5W). Urine production, GFR, and fractional excretion (FE) of solutes were measured for 10 hours. RESULTS: For all protocols, urine production significantly (P < .001) increased after bolus injection, but no significant difference in urine production or GFR was observed among the treatment groups. Mannitol injection increased the FE of sodium and urea nitrogen, but these effects were short-lived. CONCLUSIONS: Mannitol has minimal effect on urine production and GFR but does increase FE of urea nitrogen and sodium, immediately after bolus injection. Constant rate infusion at a conventional dosage of 1 mg/kg/min cannot maintain these effects in dogs with normal renal function, because mannitol concentration decreases rapidly.

A Comparative Study of Bolus Dose of Hypertonic Saline, Mannitol, and Mannitol Plus Glycerol Combination in Patients with Severe Traumatic Brain Injury.

BACKGROUND: This prospective randomized controlled study compared the efficacy of an equiosmolar and isovolumetric dose of 3% hypertonic saline, 20% mannitol, and 10% mannitol plus 10% glycerol combination in reducing the raised intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI). METHODS: A total of 120 patients of severe TBI with increased ICP were randomized to receive an equiosmolar and isovolumetric dose of 3% hypertonic saline, 20% mannitol, and 10% mannitol plus 10% glycerol combination at a defined infusion rate, which was stopped when ICP was <15 mm Hg. RESULTS: A total of 120 patients with severe TBI (aged >18 years, Glasgow Coma Scale ≤8, and had sustained elevated ICP of >20 mm Hg for more than 5 minutes) were randomized during the study. All data were presented as mean (minimum-maximum). A one-way analysis of variance test was used to analyze the effect across the treatment group, and Tukey's method was used for multiple comparisons. A paired t-test was employed to analyze the effect of the medication within each group. All 3 drugs decreased ICP below 15 mm Hg (P < 0.0001). The maximum change in ICP occurred after a bolus dose of 3% hypertonic saline followed by 10% mannitol plus 10% glycerol combination and then 20% mannitol (60% vs. 57% vs. 55%, respectively). Mean arterial pressure and cerebral perfusion pressure were increased after the bolus dose of study medications. Maximum changes occurred after infusion of 3% hypertonic saline followed by 10% mannitol plus 10% glycerol combination and 20% mannitol (P < 0.0349 and <0.0013, respectively). There was no statistically significant change in the hematocrit value noted after the bolus dose of any of the study medications. Serum sodium and osmolarity were raised significantly after the bolus dose of study medications. Maximum changes in serum sodium and osmolarity occurred after the bolus dose of 3% hypertonic saline. The mean dose required to reduce ICP below 15 mm Hg for 3% hypertonic saline: 1.4 mL/kg, for 10% mannitol plus 10% glycerine: 1.7 mL/kg, and for 20% mannitol: 2.0 mL/kg. The mean time required to reduce ICP below 15 mm Hg for 3% hypertonic saline: 16 minutes, for 10% mannitol plus 10% glycerine: 19 minutes, and for 20% mannitol: 23 minutes. The maximum change in the Glasgow Coma Scale occurred after the bolus dose of 3% hypertonic saline, followed by 10% mannitol plus 10% glycerol combination and then 20% mannitol. CONCLUSIONS: All 3 osmotic compounds exhibit comparable effectiveness in reducing ICP when a similar osmotic load is administrated, but 3% hypertonic saline appeared to be more effective followed by 10% mannitol plus 10% glycerol combination and 20% mannitol. A dose of 1.4 mL/kg can be recommended as an initial bolus dose for 3% hypertonic saline. Hypertonic saline can be recommended to treat patients with pretreatment hypovolemia, hyponatremia, or renal failure. There is no clear benefit compared with 20% mannitol in regard to neurologic outcome, even though there is a minor positive trend for 3% hypertonic saline and 10% mannitol plus 10% glycerol combination.

Focus on neonatal and infantile onset of nephrogenic syndrome of inappropriate antidiuresis: 12 years later.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD), first described in 2005, is a rare genetic X-linked disease, presenting with hyponatremia, hyposmolarity, euvolemia, inappropriately concentrated urine, increased natriuresis, and undetectable or very low arginine-vasopressine (AVP) circulating levels. It can occur in neonates, infants, or later in life. NSIAD must be early recognized and treated to prevent severe hyponatremia, which can show a dangerous impact on neonatal outcome. In fact, it potentially leads to death or, in case of survival, neurologic sequelae. This review is an update of NSIAD 12 years after the first description, focusing on reported cases of neonatal and infantile onset. The different molecular patterns affecting the AVP receptor 2 (V2R) and determining its gain of function are reported in detail; moreover, we also provide a comparison between the different triggers involved in the development of hyponatremia, the evolution of the symptoms, and modality and efficacy of the different treatments available.