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.

The effect of a mixture of 2.7% sorbitol-0.54% mannitol solution on blood coagulation: an invitro, observational healthyvolunteer study using rotational thromboelastometry (ROTEM).

BACKGROUND: We investigated the effect of irrigation fluid on coagulation according to the hemodilution level using rotational thromboelastometry (ROTEM). METHODS: Venous blood was taken from 12 healthy volunteers and divided into four specimen tubes that were diluted to various levels (0%, 10%, 20%, and 40%) using an irrigation fluid composed of 2.7% sorbitol and 0.54% mannitol. RESULTS: Significant prolongation of clotting time was observed in the 40% diluted sample using both INTEM (P = 0.009) and EXTEM (P = 0.001) assays. However, the clot formation time was prolonged significantly in the 10%, 20%, and 40% diluted samples using both INTEM (P < 0.001) and EXTEM (P = 0.002, P < 0.001, and P < 0.001, respectively) assays. A significant decrease of α-angle of INTEM and EXTEM were observed in the 10% (P < 0.001), 20% (P < 0.001 and P = 0.001, respectively), and 40% (P < 0.001) groups compared with the 0% dilution group. The maximum clot firmness (MCF) of INTEM decreased significantly in the 20% (P < 0.001) and 40% (P < 0.001) diluted samples. In the MCF of EXTEM and FIBTEM assays, 10% (P = 0.009 and P = 0.015, respectively), 20% (P = 0.001), and 40% (P < 0.001) samples showed a significant decrease compared with the 0% sample. Nevertheless, most of the ROTEM values were within the reference range, except the 40% sample. CONCLUSIONS: Blood became hypocoagulable when it was diluted in vitro with a fluid composed of 2.7% sorbitol and 0.54% mannitol.

[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.

Preparation and evaluation of poly(lactic-co-glycolic acid) microparticles as a carrier for pulmonary delivery of recombinant human interleukin-2: II. In vitro studies on aerodynamic properties of dry powder inhaler formulations.

OBJECTIVE: The aim of this study was the preparation and evaluation of dry powder formulations of recombinant human interleukin-2 (rhIL-2)-loaded microparticles to be administered to the lung by inhalation. METHODS: As indicated in our previous study, the microparticles were prepared by modified water-in-oil-in-water (w(1)/o/w(3)) double emulsion solvent extraction method using poly(lactic-co-glycolic acid) (PLGA) polymers. The dry powder formulations were prepared with blending of microparticles and mannitol as a coarse carrier. The actual aerodynamic characteristics of the microparticles alone and prepared mixtures with mannitol are evaluated by using the eight-stage Andersen cascade impactor. RESULTS: Due to the low tapped density of microparticles (<0.4 g/cm(3)), the theoretical aerodynamic diameter (MMADt) values were calculated (<5 µm) on the basis of the geometrical particle diameter and tapped density values. The lowest tapped density value (0.17 g/cm(3)) belongs to the cyclodextrin-containing formulation. According to the results obtained using the cascade impactor, the emitted doses for all microparticle formulations were found to be rather high and during the aerosolization for all the formulations except F3 and F5, >90% of the capsule content was determined to be released. However, the actual aerodynamic diameter (MMADa) values were seen to be higher than the MMADt values. The blending of the microparticles with mannitol allowed their aerodynamic diameters to decrease and their fine particle fraction values to increase. CONCLUSION: The obtained results have shown that the mixing of rhIL-2-loaded microparticles with mannitol possess suitable aerodynamic characteristics to be administered to the lungs by inhalation.

Time course of dehydrating effects of isosorbide on experimentally induced endolymphatic hydrops in guinea pigs.

Osmotic diuretics are therapeutic agents used to reduce endolymphatic hydrops. However, glycerol-induced change in endolymph volume is followed by a rebound phenomenon. In this study, we investigated the rebound phenomenon occurring with isosorbide, an osmotic diuretic used as a therapeutic agent for Ménière's disease in Japan. Forty guinea pigs underwent surgical obliteration of the endolymphatic sac. Thirty received isosorbide orally 1 month after surgery. These animals were sacrificed 3, 6, or 12 h after isosorbide intake. The remaining 10 animals served as controls. Quantitative assessment of changes in the endolymphatic space was performed light-microscopically. Isosorbide reduced cochlear endolymph volume, with a peak reduction 6 h after intake. Thereafter, no prominent rebound phenomenon was noted. Clinically, since isosorbide is orally administered every 8 h, rebound phenomenon need not be considered in the treatment with isosorbide.

Excipient crystallinity and its protein-structure-stabilizing effect during freeze-drying.

The relationship between mannitol crystallization during freeze-drying and its effects on stabilizing protein structures was studied using lysozyme, bovine serum albumin, ovalbumin, beta-lactoglobulin and lactate dehydrogenase as model proteins. FT-IR analysis of the protein secondary structure indicated perturbation of both alpha-helix and beta-sheet regions in freeze-drying without cosolutes, whereas the proteins retained most of their native structure in co-lyophilization with sucrose. Mannitol protected the protein structure to different degrees depending on the crystallinity. The combination of mannitol with potassium phosphate buffer reduced the mannitol crystallinity and the structural changes occurring during freeze-drying, whereas mannitol by itself showed little stabilizing effect. Heat-treatment of the frozen solutions at -10 degrees C resulted in a higher mannitol crystallinity and a smaller stabilizing effect in freeze-drying. The secondary structure perturbation was mostly reversible in rehydrated solutions. The varied structure-stabilizing effects of mannitol paralleled its effects on maintaining lower concentrations of enzyme activity during freeze-drying. These results confirm the contribution of molecular interactions between amorphous excipients and proteins (e.g. hydrogen bonding) to structure stabilization during freeze-drying.

Influence of particle size, air flow, and inhaler device on the dispersion of mannitol powders as aerosols.

PURPOSE: To study the effect of particle size, air flow and inhaler type on the dispersion of spray dried mannitol powders into aerosols. METHODS: Mannitol powders were prepared by spray drying. The solid state properties of the powders were determined by laser diffraction, X-ray powder diffraction, scanning electron microscopy, freeze fracture, Karl Fischer titration and gas pycnometry. The powders were dispersed using Rotahaler and Dinkihalerg, connected to a multistage liquid impinger at different air flows. RESULTS: Three crystalline mannitol powders with primary particle size (MMD) 2.7, 5.0, 7.3 microm and a similar polydispersity were obtained. The particles were spherical with a density of 1.5 g/cm3 and a moisture content of 0.4 wt.%. At an air flow of 30 L/min all the powders were poorly dispersed by both inhalers. With the Rotahaler increasing the flow (60-120 L/min) increased the fine particle fraction (FPF) in the aerosols for the 2.7 microm powder, and decreased the FPF for the 7.3 microm powder; whereas the FPF for 5.0 microm powder was unaffected. With the Dinkihaler, all the powders were near complete dispersion at > or = 60 L/min. CONCLUSIONS: The FPF in the mannitol powder aerosols was determined by an interplay of the particle size, air flow and inhaler design.

Deoxycholate-hydrogels: novel drug carrier systems for topical use.

Na-deoxycholate (Na-DOC) forms a viscous thixotropic gel when in contact with excess buffer systems. The resulting gels have been tested as novel drug carrier systems for topical use. The influence of differing amounts of mannitol, glycerol and xylitol on the viscous modulus (G"/Pa) was evaluated by oscillatory measurements. Na-DOC (0.5%) in phosphate buffered saline (PBS) with 5% mannitol was chosen as an optimised formulation, taking into account viscosity, distribution and appearance. The release rate of the model drug rutin through an artificial membrane was higher than those from hydroxyethylcellulose- (HEC) and sodium polyacrylate (NaC934)-gels; permeation through excised rat skin was also highest for the Na-DOC systems. The results indicate that Na-DOC significantly increases the membrane permeability. The microbial stability was in the same range as HEC- and NaC934-gels, making a preservation necessary. Na-DOC-gels are novel low molecular weight, multifunctional drug carriers, which also act as penetration enhancers. Their thixotropy is an additional advantage for better application to large skin areas, nasal, vaginal and buccal membranes. Therefore, Na-DOC-gels can be considered promising, alternative drug carrier systems for topical pharmaceutical as well as cosmetic use.

Mannitol and cardiac surgery.

Mannitol is widely used in all fields of medicine, due to its beneficial actions on the kidney and brain. Mannitol has been extensively used in cardiac surgery since its infancy, and remains in common usage to day. Mannitol is mainly used for its effects on the kidneys, but it has actions on the brain, lungs, heart, gastrointestinal tract and the red cell. Mannitol also has effects on free radicals and nitric oxide. As with virtually all treatments in medicine and surgery its use is not immune from side effects. The medical literature on mannitol over the past 30 years is considered.

Incidence of perforation and other mechanical complications during dual active fixation.

The intraoperative and early postoperative mechanical complications of a procedure combining an atrial screw-in lead and a ventricular screw-in lead insertion were prospectively evaluated. The procedure was performed in 119 consecutive patients (mean age 69 +/- 8 years), at first implant in 100 patients and at reoperation in 19. Nine patients had previously undergone cardiac surgery and three underwent transvenous ventricular defibrillator implantation. The double sets of leads were introduced through 2 separate veins in 5 cases, through a single venous route in 114 cases, using a percutaneous approach in 75 cases and a venous cutdown in 49, and a guidewire procedure following the venotomy in 19. The screw was mannitol coated in 102 cases, exposed in 111, and extendable/retractable in 25. The fixation of the ventricular lead was performed at the apex in 108 cases, at the outflow tract in 11, and was followed by the fixation of the atrial lead at the appendage in 112 cases and at the lateral wall in 7 cases. The lead positioning and fixation were successful at first attempt in 103 cases and after repeated lead manipulation in 19 cases. The rotational torque could be transferred to the helix in all cases except in one patient who required a second vein puncture. Unintentional fixation in the ventricular chamber with subsequent failure to remove the lead occurred in one patient. Reoperation for lead dislodgment was required in two patients. In one patient, symptomatic pericarditis with pericardial effusion was observed 1 day after the procedure and resolved spontaneously. Dual active fixation is feasible with a low incidence of mechanical complications.