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.

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.

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.

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.

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.

Effects of Osmotic Therapy on Pupil Reactivity: Quantification Using Pupillometry in Critically Ill Neurologic Patients.

BACKGROUND: Osmotic therapy is a critical component of medical management for cerebral edema. While up to 90% of neurointensivists report using these treatments, few quantitative clinical measurements guide optimal timing, dose, or administration frequency. Its use is frequently triggered by a qualitative assessment of neurologic deterioration and/or pupil size, and anecdotally appears to improve pupil asymmetry suggestive of uncal herniation. However, subjective pupil assessment has poor reliability, making it difficult to detect or track subtle changes. We hypothesized that osmotic therapy reproducibly improves quantitative pupil metrics. METHODS: We included patients at two centers who had recorded quantitative pupil measurements within 2 h before and after either 20% mannitol or 23.4% hypertonic saline in the neurosciences intensive care unit. The primary outcome was the Neurologic Pupil Index (NPi), a composite metric ranging from 0 to 5 in which > 3 is considered normal. Secondary outcomes included pupil size, percent change, constriction and dilation velocity, and latency. Results were analyzed with Wilcoxon signed-rank tests, Chi-square and multi-level linear regression to control for other edema-reducing interventions. RESULTS: Out of 72 admissions (403 paired pupil observations), NPi significantly differed within 2 h of osmotic therapy when controlling for other commonly used interventions in our whole cohort (ß = 0.08, p = 0.0168). The effect was most pronounced (ß = 0.57) in patients with abnormal NPi prior to intervention (p = 0.0235). CONCLUSIONS: Pupil reactivity significantly improves after osmotic therapy in a heterogenous critically ill population when controlling for various other interventions. Future work is necessary to determine dose-dependent effects and clinical utility.

Cardiac output changes after osmotic therapy in neurosurgical and neurocritical care patients: a systematic review of the clinical literature.

AIM: Osmotherapy constitutes a first-line intervention for intracranial hypertension management. However, hyperosmolar solutes exert various systematic effects, among which their impact on systemic haemodynamics is poorly clarified. This review aims to appraise the clinical evidence of the effect of mannitol and hypertonic saline (HTS) on cardiac performance in neurosurgical and neurocritical care patients. METHOD: A database search was conducted to identify randomized clinical trials and observational studies reporting HTS or mannitol use in acute brain injury setting. The primary end-points were alterations of cardiac output (CO) and other haemodynamic variables, while the impact of osmotic agents on intracranial pressure, brain relaxation, plasma osmolality, electrolyte levels and urinary output constituted secondary outcomes. RESULTS: Eight studies, enrolling 182 patients in total, were included. HTS exerted a more profound cardiac output augmentation than mannitol, but no distinct difference between groups occurred. Central venous pressure, stroke volume and stroke volume variation were favourably affected by both osmotic agents, whilst the reported changes in blood pressure were inconclusive. HTS infusion yielded a larger intracranial pressure reduction than mannitol but had an equivalent effect on brain relaxation. Mannitol presented a more potent diuretic effect than HTS. Effect on serum osmolality was alike in both osmotic agents, but contrary to HTS-promoted hypernatraemia, mannitol use induced transient hyponatraemia. CONCLUSIONS: Mannitol or HTS administration seems to induce an enhancement of cardiac performance; being more prominent after HTS infusion. This effect combined with mannitol-induced enhancement of diuresis and HTS-promoted increase of plasma sodium concentration could partially explain the effects of osmotherapy on cerebral haemodynamics.

Evaluation of Risk of Injury by Extravasation of Hyperosmolar and Vasopressor Agents in a Rat Model.

Inadvertent leakage of noncytotoxic agents causes severe tissue injury. In this study, we macroscopically and histopathologically evaluated the extent of skin injury caused by extravasation of hyperosmolar or vasopressor agents in rats. Rats were intradermally administered saline (100 µL), the hyperosmolar agents mannitol (5-20 mg/100 µL) and glucose (5-50 mg/100 µL), or the vasopressors dopamine (2 mg/100 µL), adrenaline (0.1 mg/100 µL), and noradrenaline (0.1 mg/100 µL). Lesion size (erythema, induration, ulceration, and necrosis) was monitored after agent injection. Skin tissue biopsies were evaluated at 24 h after agent injection. Mannitol and glucose induced severe lesions in a concentration (and osmolarity)-dependent manner. Mannitol and glucose at 10-20% (w/v) induced inflammation, and lesions healed within 3-6 d. In contrast, ≥25% (w/v) glucose elicited severe skin lesions with ulceration and necrosis within 24 h, which healed gradually 16-22 d after injection. The severity of extravasation injury caused by vasopressors varied. Adrenaline and noradrenaline induced severe injury with ulceration and necrosis, which healed over 23.3 and 18.3 d, respectively. In contrast, dopamine induced erythema and induration, and damage duration was only 5.7 d. In conclusion, mannitol and glucose at osmolarities of 549-1098 and 833-1110 mOsm/L, respectively, can be classified as "irritants," while ≥1388 mOsm/L glucose can be classified as a "vesicant." As for vasopressors, adrenaline and noradrenaline can be classified as "vesicants" whereas dopamine can be classified as an "irritant."

Impact of intestinal mannitol on hyperammonemia, oxidative stress and severity of hepatic encephalopathy in the ED.

Hyperammonemia results from hepatic inability to remove nitrogenous products generated by protein metabolism of intestinal microbiota, which leads to hepatic encephalopathy (HE) in chronic liver disease (CLD). In ammonium neurotoxicity, oxidative stress (OxS) plays a pathogenic role. Our objective was to evaluate if intestinal mannitol is as effective and safe as conventional treatment for diminishing hyperammonemia, OxS, and HE in patients with CLD. MATERIAL AND METHODS: We included 30 patients with HE classified by "Haven Criteria for Hepatic Encephalopathy". They were randomized into two groups: 1) Mannitol Group (MG) with mannitol 20% administered into the intestine by an enema, 2) conventional group (CG) with lactulose 40 g enema both substances were diluted in 800 mL of double distilled solution every 6 h; all patients received neomycin. We evaluated ammonia concentration, plasma oxidative stress, HE severity, intestinal discomfort and adverse effects. RESULTS: Hyperammonemia (171 ±â€¯104 vs 79 ±â€¯49 µmol ammonia/L, p < 0.01), and oxidative stress (MDA 29 vs 27%, formazan 15 vs 11%, carbonyls 16 vs 9% and dityrosines 10 vs 5%) were reduced in MG and CG respectively. The HE severity decreased by two degrees compared to baseline values in both groups. Intestinal discomfort and electrolyte plasma alterations were less frequent (p < 0.05) in MG than CG. CONCLUSIONS: Intestinal mannitol is as effective and safe as conventional treatment for reducing hyperammonemia, oxidative stress, and hepatic encephalopathy of CLD patients in the emergency room. Likewise, mannitol is better tolerated than conventional treatment.

Mannitol and Hypertonic Saline Reduce Swelling and Modulate Inflammatory Markers in a Rat Model of Intracerebral Hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) leaves most survivors dependent at follow-up. The importance of promoting M2-like microglial responses is increasingly recognized as a key element to ameliorate brain injury following ICH. The osmotherapeutic agents, mannitol and hypertonic saline (HTS), which are routinely used to reduce intracranial pressure, have been shown to reduce neuroinflammation in experimental ischemic and traumatic brain injury, but anti-inflammatory effects of osmotherapies have not been investigated in ICH. METHODS: We studied the effects of iso-osmotic mannitol and HTS in rat models of ICH utilizing high-dose and moderate-dose collagenase injections into the basal ganglia, associated with high and low mortality, respectively. We studied the effects of osmotherapies, first given 5 h after ICH induction, and then administered every 12 h thereafter (4 doses total). Immunohistochemistry was used to quantify microglial activation and polarization. RESULTS: Compared to controls, mannitol and HTS increased plasma osmolarity 1 h after infusion (301 ± 1.5, 315 ± 4.2 and 310 ± 2.0 mOsm/kg, respectively), reduced mortality at 48 h (82, 36 and 53%, respectively), and reduced hemispheric swelling at 48 h (32, 21, and 17%, respectively). In both perihematomal and contralateral tissues, mannitol and HTS reduced activation of microglia/macrophages (abundance and morphology of Iba1 + cells), and in perihematomal tissues, they reduced markers of the microglia/macrophage M1-like phenotype (nuclear p65, TNF, and NOS2), increased markers of the microglia/macrophage M2-like phenotype (arginase, YM1, and pSTAT3), and reduced infiltration of CD45 + cells. CONCLUSIONS: Repeated dosing of osmotherapeutics at regular intervals may be a useful adjunct to reduce neuroinflammation following ICH.

Intravenous mannitol in status migrainosus treatment: a clinical case series.

Status migrainosus (SM) is defined as a severe migraine attack, usually poorly responsive to treatments, lasting more than 72 h. Recurrent SM predicts chronic migraine (CM) development in 83.7% of cases. There is evidence that in most unresponsive CM patients a sinus stenosis-associated raised intracranial pressure is causatively involved in migraine chronification. To test the hypothesis that SM may reflect a sustained rise in intracranial pressure, we tested the efficacy of a 3-day treatment with intravenous mannitol 18% 250 ml b.i.d. in seven subjects presenting with a SM unresponsive to common treatments, showing unilateral or bilateral sinus stenosis at magnetic resonance venography. Mannitol infusion induced the abrupt reduction or the disappearance of pain in all patients, at least along the 3 days of treatment. While the benefit was only observed during the days of treatment in two subjects, in the remaining five patients the time to the next headache was delayed between 20 days to 5 weeks after mannitol infusion. Due to the lack of any analgesic property of mannitol, our data indicate that in this series a rise in intracranial pressure was involved in SM causative mechanisms.

A Systematic Review of Randomized Controlled Trials Comparing Hypertonic Sodium Solutions and Mannitol for Traumatic Brain Injury: Implications for Emergency Department Management.

OBJECTIVE: To comparatively evaluate hypertonic sodium (HTS) and mannitol in patients following acute traumatic brain injury (TBI) on the outcomes of all-cause mortality, neurological disability, intracranial pressure (ICP) change from baseline, ICP treatment failure, and serious adverse events. DATA SOURCES: PubMed, EMBASE, CENTRAL, Cochrane Database of Systematic Reviews, ClinicalTrials.gov, and WHO ICTRP (World Health Organization International Clinical Trials Registry Platform) were searched (inception to November 2015) using hypertonic saline solutions, sodium chloride, mannitol, osmotic diuretic, traumatic brain injury, brain injuries, and head injury. Searches were limited to humans. Clinical practice guidelines and bibliographies were reviewed. STUDY SELECTION AND DATA EXTRACTION: Prospective, randomized trials comparing HTS and mannitol in adults (≥16 years) with severe TBI (Glasgow Coma Scale score ≤8) and elevated ICP were included. ICP elevation, ICP reduction, and treatment failure were defined using study definitions. DATA SYNTHESIS: Of 326 articles screened, 7 trials enrolling a total of 191 patients met inclusion criteria. Studies were underpowered to detect a significant difference in mortality or neurological outcomes. Due to significant heterogeneity and differences in reporting ICP change from baseline, this outcome was not meta-analyzed. No difference between HTS and mannitol was observed for mean ICP reduction; however, risk of ICP treatment failure favored HTS (risk ratio [RR] = 0.39; 95% CI = 0.18-0.81). Serious adverse events were not reported. CONCLUSIONS: Based on limited data, clinically important differences in mortality, neurological outcomes, and ICP reduction were not observed between HTS or mannitol in the management of severe TBI. HTS appears to lead to fewer ICP treatment failures.

Safety of a short hydration method for cisplatin administration in comparison with a conventional method-a retrospective study.

OBJECTIVE: Cisplatin is administered in combination with massive hydration to avoid renal toxicity, making its administration difficult in an outpatient setting. Although a short hydration protocol for cisplatin has been recently developed, its safety is not fully understood. METHODS: Consecutive patients with lung or other cancer and an Eastern Cooperative Oncology Group performance status of 0-2 who were receiving chemotherapy containing cisplatin at a dose of ≥60 mg/m(2) in a single administration were evaluated. Seventy-four patients were treated with a short hydration protocol consisting of 1750-2250 ml of hydration with mannitol and magnesium supplementation over a period of 3.75-4.75 h on Day 1. Sixty-nine patients were treated with a conventional hydration protocol consisting of 2100-2600 ml of hydration over 6.5-7.5 h on Day 1 with pre- and post-hydration on Days 0, 2 and 3. Toxicity was then compared between the two groups. RESULTS: An elevated serum creatinine level ≥grade 1 was significantly less frequent in the group receiving the short hydration protocol than in the group receiving conventional hydration. Other toxicities were similar between the two groups. Consequently, the completion rate for the planned treatment in the short hydration group (73.0%, 54/74) was significantly higher than that in the conventional hydration group (53.6%, 37/69). CONCLUSIONS: Short hydration is safe, making cisplatin-containing chemotherapy easier to perform.

Mannitol to prevent cisplatin-induced nephrotoxicity in patients with squamous cell cancer of the head and neck (SCCHN) receiving concurrent therapy.

PURPOSE: The purpose of this study is to compare the incidence and severity of nephrotoxicity in patients receiving cisplatin with saline hydration vs. saline hydration with mannitol. METHODS: Retrospective chart review of all patients receiving a starting dose of cisplatin 100 mg/m(2) with concurrent radiation for SCCHN between January 1, 2009 and March 1, 2013. All patients received pre and post hydration each with 1 l of 0.9 % saline. The mannitol group received 12.5 g of mannitol in the prehydration fluid. The primary outcome was to compare the rate of grade 3 or greater serum creatinine (SCr) increase in patients receiving saline hydration vs. the addition of mannitol; additional parameters of interest included creatinine clearance, electrolyte disturbances, dose changes, and discontinuation of cisplatin. RESULTS: Data from 139 patients (80 % male) with a median age of 56 years (range 22 to 75 years) were collected; 88 received mannitol and 51 received saline alone. On multivariable analysis, the mannitol group was less likely to have grade 3 SCr increase than saline only group (OR 0.16; 95 % CI 0.04-0.65; p value = 0.01). There were no grade 4 SCr increase events. Rates of hypomagnesemia and hypokalemia were similar across groups. Grade 3 hyponatremia was more likely to occur in the mannitol group as compared to saline alone group (41 vs 22 %; p = 0.026). CONCLUSION: The addition of mannitol to saline hydration decreased the incidence of grade 3 increases in SCr in this cohort of patients and may increase rates of hyponatremia. Further investigations of methods to lessen cisplatin-induced nephrotoxicity are needed.

Efficacy of Intravenous Mannitol in the Management of Orbital Compartment Syndrome: A Nonhuman Primate Model.

PURPOSE: To report the efficacy of intravenous mannitol in the treatment of orbital compartment syndrome. METHODS: An experimental study was conducted on 4 nonhuman primates (8 orbits). Orbital compartment syndrome was simulated by injecting autologous blood into both orbits of each nonhuman primate until a pressure of 80 mm Hg was reached (time 0). After 10 minutes, nonhuman primates were randomized to receive an infusion of either mannitol or saline, given over 15 minutes. Five minutes after the infusion was complete, lateral canthotomy and cantholysis was performed on both orbits in isolated steps every 5 minutes. During the study protocol, orbital and intraocular pressures were recorded every 5 minutes, with a final set of measurements at 60 minutes. The primary outcome measures were the mean change in pressure from time 0 to 60 minutes, as well as the mean change in pressure during the infusion period. RESULTS: There was no statistically significant difference in the mean changes in orbital or intraocular pressure from time 0 to 60 minutes of the protocol. However, during the infusion period there was significantly greater decrease in both orbital and intraocular pressure in the mannitol compared with saline group (-34.0 vs. -9.3 mm Hg for orbital pressure [p = 0.03]; -34.8 vs. -9.7 mm Hg for intraocular pressure [p = 0.04]). CONCLUSIONS: While the definitive treatment of orbital compartment syndrome is lateral canthotomy and cantholysis, mannitol results in a rapid and clinically meaningful drop in orbital and intraocular pressure. The authors believe that their data support the routine use of mannitol in orbital compartment syndrome, especially when there is a delay in timely surgical management.

Hypertonic saline in elevated intracranial pressure: past, present, and future.

Hypertonic Saline (HS) has been a proven and effective therapy and a safe alternative to mannitol in patients with increase intracranial pressure (ICP). We hereby present a case of 25-year-old women with intracranial bleed secondary to right parietal arteriovenous malformation. Patient underwent surgery for evacuation of hematoma and resection of arteriovenous malformation. Post- operative course was complicated by recurrent episodes of elevated ICP. She received total of 17 doses of 23.4% HS and 30 doses of mannitol with good outcome. Despite reluctance from some clinicians to use HS, hypertonic saline seems to be a safe and effective therapy.

The Role of Osmotic Therapy in Hemispheric Stroke.

BACKGROUND: Decompressive hemicraniectomy (DHC) can be lifesaving in hemispheric stroke complicated by cerebral edema. Conversely, osmotic agents have not been shown to improve survival, despite their widespread use. It is unknown whether medical measures can similarly confer survival in certain patient subgroups. We hypothesized that osmotic therapy (OT) without DHC may be associated with a greater likelihood of survival in particular populations depending on demographic, radiologic, or treatment characteristics. METHODS: We performed a retrospective cohort analysis of patients with large anterior circulation strokes with an NIH stroke scale (NIHSS) ≥10 who received OT. We compared clinical, radiologic, and treatment characteristics between two groups: (1) those who survived until discharge with only OT (medical management success) and (2) those who required either DHC or died (medical management failure). RESULTS: Thirty patients met eligibility criteria. Median NIHSS was 19 [interquartile range (IQR) 13-24], and median GCS was 10 [IQR 8-14]. Forty-seven percent of the medical management cohort survived to discharge. Demographic characteristics associated with medical management success included NIHSS (p = 0.009) and non-black race (p = 0.003). Of the various interventions, the administration of OT after 24 hours and a smaller hypertonic saline dose was also associated with survival to discharge (p = 0.038 and 0.031 respectively). CONCLUSION: Our results suggest that patients with moderate size hemispheric infarcts on presentation and those who do not require OT within the first 24 h of stroke may survive until discharge with medical management alone. Black race was also associated with conservative management failure, a finding that may reflect a cultural preference toward aggressive management. Further prospective studies are needed to better establish the utility of medical management of hemispheric edema in the setting of moderate size hemispheric infarcts.

Mannitol and renal dysfunction after endovascular aortic aneurysm repair procedures: a randomized trial.

OBJECTIVE: Endovascular aortic aneurysm repair (EVAR) may result in deterioration of renal function. Mannitol has renovascular and antioxidant properties that could prove beneficial in this respect. DESIGN: A randomized prospective study. SETTING: Attikon University Hospital, single institution. PARTICIPANTS: Eighty-six patients undergoing elective EVAR under regional anesthesia. METHODS: Patients received hydration alone (controls) or hydration plus mannitol (0.5 g/kg). MEASUREMENTS AND MAIN RESULTS: Creatinine, serum cystatin-C, urine neutrophil-gelatinase-associated lipocalin (NGAL), albuminuria and serum urea were measured 24 hours and 72 hours after the procedure (baseline NGAL was measured in 19 randomly selected patients). Serum creatinine also was measured at the followup of the patients. Serum creatinine and cystatin-C were lower in the mannitol group at 24 hours postoperatively (creatinine, mannitol [n=43]; 1.07±0.26 [CI95%: 0.99-1.15] v controls [n=43]; 1.20±0.30 [CI95%: 1.11-1.30]), but not at 72 hours (creatinine, mannitol [n=43]; 1.13±0.29 [CI95%: 1.04-1.22] v controls [n=43]; 1.26±0.41 [CI95% 1.15-1.38]). Urine NGAL increased substantially at 24 hours without differences between groups. At followup (controls: 13±7 months; mannitol: 12±7 months), there were no differences between creatinine or creatinine clearance (creatinine: controls [n=28]; 1.15±0.39 [CI95% 1.02-1.29] v mannitol [n=23]; 1.05±0.27 [CI95%: 0.95-1.17]). The overall changes of creatinine and creatinine clearance with time were significant in controls but not in the mannitol group. The classification according to the RIFLE criteria yielded 4 patients at risk for renal injury and 2 with renal injury in the control group and 6 patients at risk with no patients with injury in the mannitol group, but the difference of renal dysfunction between the 2 groups was not statistically significant. CONCLUSIONS: Mannitol plus hydration during EVAR provides a small but significant benefit for renal function. Future preventive protocols aiming at greater restoration of renal function after EVAR could include mannitol as a useful component.

[Dry powder inhalers in cystic fibrosis]. / Trockenpulverinhalation bei Mukoviszidose.

Inhaled medications play an important role in the daily treatment of patients with cystic fibrosis (CF). The classic route of administration was nebulisation via jet nebulisers. Respiratory delivery of fluid particles should loosen the viscid respiratory secretions, making airway clearance via cough or physiotherapy more efficient. Until recently, only jet nebulisers allowed to administer high doses of aerosolised antipseudomonal antibiotics. Powder inhalers for the treatment of cystic fibrosis have recently been made available. The newly developed powders and inhalers differ considerably from conventional dry powder inhalers used for the treatment of chronic obstructive airway disease. The present article will review two inhaled antibiotics, i. e. tobramycin and colistin, and the hyperosmotic agent mannitol, which increases the hydration of the airways. Topics are particle engineering, efficacy and tolerability results from clinical trials, as well as functional and practical aspects related to these new drugs.