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Aflibercept (AFL) is an Fc fusion protein used in the treatment of colorectal cancers and different ophthalmological diseases. There are two medicines in which AFL is the active substance: Zaltrap and Eylea, referred as ziv-AFL and AFL respectively. No proper accelerated degradation studies were published on either AFL or ziv-AFL. These studies are essential during research, development and manufacturing stages. Here, we characterized ziv-AFL and submitted it to different stress conditions: light, 60 °C, freeze-thaw cycles, changes in pH, high hypertonic solution and strong denaturing conditions. We used an array of techniques to detect aggregation (SE-HPLC/DAD and DLS), changes in secondary structure (Far-UV circular dichroism), changes in conformation or tertiary structure (Intrinsic tryptophan fluorescence) and alterations in functionality (ELISA). Results indicate that aggregation is common degradation pathway. Two different types of aggregates were detected: dimers and high molecular weight aggregates attributed to β-amyloid-like structures. Secondary structure was maintained in most of the stress tests, while conformation was altered by almost all the tests except for the freeze-thaw cycles. Functionality, evaluated by its immunochemical reaction with VEGF, was found to be stable but with decrease when exposed to light and with likely partial inactivation of the drug when pH was altered.

Hypoxia plays a role in the pathogenesis of acute kidney injury under diverse clinical settings, including nephrotoxicity. Although some nephrotoxins exert direct renal parenchymal injury, likely with consequent altered oxygenation, others primarily reduce renal parenchymal oxygenation, leading to hypoxic tubular damage. As outlined in this review, nephrotoxin-related renal hypoxia may result from an altered renal oxygen supply (cyclosporine), enhanced oxygen consumption for tubular transport (agents inducing osmotic diuresis), or their combination (nonsteroidal anti-inflammatory drugs, radiocontrast agents, and others). Most agents causing hypoxic renal injury further supress physiologic low medullary Po 2 , in which a limited regional blood supply barely matches the intense regional tubular transport and oxygen consumption. The medullary tubular transport and blood supply are finely matched, securing oxygen sufficiency. Predisposition to hypoxia-mediated nephrotoxicity by medical conditions, such as chronic kidney disease or diabetes, may be explained by malfunctioning of control systems that normally maintain medullary oxygenation. However, this propensity may be diminished by hypoxia-mediated adaptive responses governed by hypoxia-inducible factors. Recent reports have suggested that inhibitors of sodium-glucose cotransporters and the administration of hypertonic saline may be added to the growing list of common therapeutic interventions that intensify medullary hypoxia, and potentially could lead to hypoxic acute kidney injury., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Mannitol is the most commonly used intraoperative hypertonic solution in patients undergoing craniotomy. However, its use has been reported to be associated with hyperkalemia, which can occasionally be life threatening., Case Description and Literature Review: In this report, we discuss the case of a patient who had intraoperative cardiac arrest secondary to mannitol-induced hyperkalemia during a craniotomy for tumor resection. In addition, we provide a comprehensive review of the literature concerning similar cases previously reported, as well as a discussion of the pathophysiology of mannitol-induced hyperkalemia. Review of the literature suggests that patients prone to this phenomenon are young and healthy individuals with normal preoperative and postoperative cardiopulmonary and renal functions. The literature also suggests that the total dose of mannitol, as well as its rate of infusion, may play a role in the development of this phenomenon., Conclusions: Knowledge of the existence of mannitol-induced hyperkalemia is paramount for the neurosurgeon and the anesthesiologist, because early treatment with insulin and calcium can quickly restore normal cardiac rhythm and prevent intraoperative death., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Physiological saline can hardly be treated as physiological as it contains qualitatively and quantitatively different amounts of electrolytes. In particular, it contains 50% more chlorine ions than serum. Physiological saline can cause metabolic acidosis and in diabetic patients hyperchloremic acidosis. In comparison with Ringer solution and plasma-lyte, physiological saline is causing higher number of untoward effects and mortality associated with surgery. Ringer solution should be used in the situations requiring expansion of extracellular fluid. Physiological saline is a solution of choice in hypochloremic alkalosis in the case of brain injuries quite unfavourable is unnecessary rapid correction with physiological saline which can lead to serious sequelae in form of brain oedema and central extrapontine myelinolysis (osmotic demyelinisation) and permanent brain lesions. The hyponatremia's treatment depends on severity of symptoms, neurological deficit motivates immediate 4-6 mmol/l infusion, but further correction should be prolonged to 24-hrs; cautious correction corresponds to 8-mmol/l for 24 hrs. The modern treatment encompasses the introduction of vasopressin receptors antagonist--vaptans., (© 2015 MEDPRESS.)

Impaired hemostasis frequently occurs after traumatic shock and resuscitation. The prehospital fluid administered can exacerbate subsequent bleeding and coagulopathy. Hypertonic solutions are recommended as first-line treatment of traumatic shock; however, their effects on coagulation are unclear. This study explores the impact of resuscitation with various hypertonic solutions on early coagulopathy after trauma. We conducted a prospective observational subgroup analysis of large clinical trial on out-of-hospital single-bolus (250 mL) hypertonic fluid resuscitation of hemorrhagic shock trauma patients (systolic blood pressure, ≤70 mmHg). Patients received 7.5% NaCl (HS), 7.5% NaCl/6% Dextran 70 (HSD), or 0.9% NaCl (normal saline [NS]) in the prehospital setting. Thirty-four patients were included: 9 HS, 8 HSD, 17 NS. Treatment with HS/HSD led to higher admission systolic blood pressure, sodium, chloride, and osmolarity, whereas lactate, base deficit, fluid requirement, and hemoglobin levels were similar in all groups. The HSD-resuscitated patients had higher admission international normalized ratio values and more hypocoagulable patients, 62% (vs. 55% HS, 47% NS; P < 0.05). Prothrombotic tissue factor was elevated in shock treated with NS but depressed in both HS and HSD groups. Fibrinolytic tissue plasminogen activator and anti-fibrinolytic plasminogen activator inhibitor type 1 were increased by shock but not thrombin-activatable fibrinolysis inhibitor. The HSD patients had the worst imbalance between procoagulation/anticoagulation and profibrinolysis/antifibrinolysis, resulting in more hypocoagulability and hyperfibrinolysis. We concluded that resuscitation with hypertonic solutions, particularly HSD, worsens hypocoagulability and hyperfibrinolysis after hemorrhagic shock in trauma through imbalances in both procoagulants and anticoagulants and both profibrinolytic and antifibrinolytic activities.

Background: Patients with brain tumour usually suffer from increased pressure in the skull due to swelling of brain tissue. A swollen brain renders surgical removal of the brain tumour difficult. To ease surgical tumour removal, measures are taken to reduce brain swelling, often referred to as brain relaxation. Brain relaxation can be achieved with intravenous fluids such as mannitol or hypertonic saline. This review was conducted to find out which of the two fluids may have a greater impact on brain relaxation., Objectives: The objective of this review was to compare the effects of mannitol versus those of hypertonic saline on intraoperative brain relaxation in patients undergoing craniotomy., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 10), MEDLINE via Ovid SP (1966 to October 2013) and EMBASE via Ovid SP (1980 to October 2013). We also searched specific websites, such as www.indmed.nic.in, www.cochrane-sadcct.org and www.Clinicaltrials.gov., Selection Criteria: We included randomized controlled trials (RCTs) that compared the use of hypertonic saline versus mannitol for brain relaxation. We also included studies in which any other method used for intraoperative brain relaxation was compared with mannitol or hypertonic saline. Primary outcomes were longest follow-up mortality, Glasgow Outcome Scale score at three months and any adverse events related to mannitol or hypertonic saline. Secondary outcomes were intraoperative brain relaxation, intensive care unit (ICU) stay, hospital stay and quality of life., Data Collection and Analysis: We used standardized methods for conducting a systematic review, as described by the Cochrane Handbook for Systematic Reviews of Interventions. Two review authors independently extracted details of trial methodology and outcome data from reports of all trials considered eligible for inclusion. All analyses were made on an intention-to-treat basis. We used a fixed-effect model when no evidence was found of significant heterogeneity between studies, and a random-effects model when heterogeneity was likely., Main Results: We included six RCTs with 527 participants. Only one RCT was judged to be at low risk of bias. The remaining five RCTs were at unclear or high risk of bias. No trial mentioned the primary outcomes of longest follow-up mortality, Glasgow Outcome Scale score at three months or any adverse events related to mannitol or hypertonic saline. Three trials mentioned the secondary outcomes of intraoperative brain relaxation, hospital stay and ICU stay; quality of life was not reported in any of the trials. Brain relaxation was inadequate in 42 of 197 participants in the hypertonic saline group and in 68 of 190 participants in the mannitol group. The risk ratio for brain bulge or tense brain in the hypertonic saline group was 0.60 (95% confidence interval (CI) 0.44 to 0.83, low-quality evidence). One trial reported ICU and hospital stay. The mean (standard deviation (SD)) duration of ICU stay in the mannitol and hypertonic saline groups was 1.28 (0.5) and 1.25 (0.5) days (P value 0.64), respectively; the mean (SD) duration of hospital stay in the mannitol and hypertonic saline groups was 5.7 (0.7) and 5.7 (0.8) days (P value 1.00), respectively, Authors' Conclusions: From the limited data available on the use of mannitol and hypertonic saline for brain relaxation during craniotomy, it is suggested that hypertonic saline significantly reduces the risk of tense brain during craniotomy. A single trial suggests that ICU stay and hospital stay are comparable with the use of mannitol or hypertonic saline. However, focus on other related important issues such as long-term mortality, long-term outcome, adverse events and quality of life is needed.

Allergic drug reactions must always be considered when prescribing treatment, even in frequent pediatric problems such as acute abdominal pain due to constipation. We describe an original case of anaphylactic shock due to the administration of hypertonic rectal enema in a child. A 9-year-old child admitted to the emergency department for an acute complaint of abdominal pain related to constipation received an administration of a hypertonic rectal enema to allow the passage of stools. Afterwards, the child presented a life-threatening episode, requiring emergency treatment with transfer to the pediatric intensive care unit, suggesting an anaphylactic shock. The absence of any other drug or food intake, the chronology of events, and favorable outcome after treatment led to the diagnosis of a probable allergy to methylparaben, sodium parahydroxybenzoate, present as the excipient in the rectal enema. Anaphylactic shock is a serious allergic reaction, setting in rapidly, which may lead to fatal outcome. Most reactions to parabens reported concern, almost exclusively, the cutaneous application of paraben-containing topical preparations. The present observation underscores the original and undescribed risk of an allergic general reaction following the rectal administration of parabens. The indications of any prescription must be carefully observed and potential drug contraindications, considering the patient's history of allergy, should be sought., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Objective: To describe anesthesia for renal transplantation that progressed to a sharp potassium increase after kidney reperfusion with Euro-Collins' solution in the operative field. We will also report on diagnosis and treatment used., Conclusion: The use of infusion solutions in the surgical field requires careful monitoring, such as electrocardiography, measurement of serum potassium, and availability of calcium gluconate, insulin, and albuterol for immediate use. The replacement of Euro-Collins' solution for saline solution immediately before the implant may be a useful option in patients with high levels of potassium.

Background: The hemodialysis (HD) population has a particularly high incidence of amputation, which is likely associated with decreased tissue oxygenation during HD. However, information about the risk factors leading to amputation in peritoneal dialysis (PD) patients is limited. Here, we have investigated the association between the use of hypertonic peritoneal dialysate (HPD) and subsequent amputation in PD patients., Methods: Based on the data from the Taiwan National Health Insurance research database, this observational cohort study enrolled 203 PD patients who had received HPD early during treatment and had not undergone amputation and 296 PD controls who had not undergone amputation. Subjects were followed through until the end of 2009 and the event rates of new non-traumatic amputation were compared between groups., Results: The incidence of amputation was 3 times higher for the HPD cohort than for the comparison cohort (23.68 vs. 8.01 per 1000 person-years). The hazard ratio (HR) for this group, estimated using a multivariable Cox model, was 2.48 (95% confidence interval [CI] = 1.06-5.79). The HR for patients with both diabetes and early adoption of HPD increased to 44.34 (95% CI = 5.51-357.03), compared to non-HPD non-diabetic PD controls., Conclusion: Early utilization of HPD in PD patients is associated with increasing risk of amputation; this risk considerably increases for those with concomitant diabetes.

Despite the fact that it has been used since the 1960s in diseases associated with brain edema and has been investigated in >150 publications on head injury, very little has been published on the outcome of osmotherapy. We can only speculate whether osmotherapy improves outcome, has no effect on outcome, or leads to worse outcome. Here we describe the action and potentially beneficial and adverse effects of the 2 most commonly used osmotic solutions, mannitol and hypertonic saline, and present some critical aspects of their use. There is a well-documented transient intracranial pressure (ICP)-reducing effect of osmotherapy, but an adverse rebound increase in ICP after its withdrawal has been discussed extensively in the literature and is an expected pathophysiological phenomenon. From side effects related to renal and pulmonary failure, electrolyte disturbances, and a rebound increase in ICP, osmotherapy can be negative for outcome, which may explain why we lack scientific support for its use. These drawbacks, and the fact that the most recent Cochrane meta-analyses of osmotherapy in brain edema and stroke could not find any beneficial effects on outcome, make routine use of osmotherapy in brain edema doubtful. Nevertheless, the use of osmotherapy as a temporary measure may be justified to acutely prevent brain stem compression until other measures, such as evacuation of space-occupying lesions or decompressive craniotomy, can be performed. This article is the Con part in a Pro-Con debate in the present journal on the general routine use of osmotherapy in brain edema.

In neonatal intensive care units, extravasation is one of the most common injuries occurring in infants as a complication of infusion therapy. These very preterm infants have immature skin which is easily damaged. They often require a longer duration of intravenous therapy, and obtaining intravenous access can be difficult. An invasive treatment should be avoided, whenever possible, particularly for very immature infants. In our Special Operative Unit for ulcers and difficult-to-heal wounds, University of Rome, we successfully treated a premature neonate, who experienced extravasation of hypertonic fluid, using dermal substitutes and products of regenerative medicine.

Objective: To determine whether out-of-hospital administration of hypertonic fluids would improve survival after severe injury with hemorrhagic shock., Background: Hypertonic fluids have potential benefit in the resuscitation of severely injured patients because of rapid restoration of tissue perfusion, with a smaller volume, and modulation of the inflammatory response, to reduce subsequent organ injury., Methods: Multicenter, randomized, blinded clinical trial, May 2006 to August 2008, 114 emergency medical services agencies in North America within the Resuscitation Outcomes Consortium., Inclusion Criteria: injured patients, age ≥ 15 years with hypovolemic shock (systolic blood pressure ≤ 70 mm Hg or systolic blood pressure 71-90 mm Hg with heart rate ≥ 108 beats per minute). Initial resuscitation fluid, 250 mL of either 7.5% saline per 6% dextran 70 (hypertonic saline/dextran, HSD), 7.5% saline (hypertonic saline, HS), or 0.9% saline (normal saline, NS) administered by out-of-hospital providers. Primary outcome was 28-day survival. On the recommendation of the data and safety monitoring board, the study was stopped early (23% of proposed sample size) for futility and potential safety concern., Results:  : A total of 853 treated patients were enrolled, among whom 62% were with blunt trauma, 38% with penetrating. There was no difference in 28-day survival-HSD: 74.5% (0.1; 95% confidence interval [CI], -7.5 to 7.8); HS: 73.0% (-1.4; 95% CI, -8.7-6.0); and NS: 74.4%, P = 0.91. There was a higher mortality for the postrandomization subgroup of patients who did not receive blood transfusions in the first 24 hours, who received hypertonic fluids compared to NS [28-day mortality-HSD: 10% (5.2; 95% CI, 0.4-10.1); HS: 12.2% (7.4; 95% CI, 2.5-12.2); and NS: 4.8%, P < 0.01]., Conclusion: Among injured patients with hypovolemic shock, initial resuscitation fluid treatment with either HS or HSD compared with NS, did not result in superior 28-day survival. However, interpretation of these findings is limited by the early stopping of the trial., Clinical Trial Registration: Clinical Trials.gov, NCT00316017.

Fleet enemas are hypertonic solutions with an osmotic action and a high concentration of phosphate. When retained in the human body they have a great toxic potential, causing severe hydro-electrolyte disorders in children, especially in newborns. We report the case of a previously healthy 8-day-old newborn who needed neonatal intensive care treatment after the inadvertent administration of an osmotically active hypertonic phosphate enema. Taking into account that phosphate removal by peritoneal dialysis (PD) strongly depends on total dialysate turnover, we chose continuous flow PD (CFPD) as the treatment option, with a successful outcome. Clinical experience with this dialytic modality is limited to a few case reports in pediatric and adult patients. To the best of our knowledge, we report here the first description of CFPD in the setting of acute phosphate nephropathy in the neonatal period. The modality of PD described here has potential as an alternative management option as it is a highly efficient, methodologically simple, and low-cost method without any need for sophisticated equipment. Physicians and parents should be aware of the adverse effects of a hypertonic phosphate enema and should never use these medications in infants and newborns.

Early preimplantation embryos are sensitive to external osmolarity and use novel mechanisms to accumulate organic osmolytes and thus control their cell volumes and maintain viability. However, these mechanisms are restricted to the cleavage stages of development, and it was unknown whether postcompaction embryos use organic osmolytes. Mouse embryos developing from the 8-cell stage formed blastocoel cavities in vitro at osmolarities up to 360 mOsM. Above this range, several putative organic osmolytes (alanine, glutamine, glycine, and beta-alanine) rescued blastocyst development, but several effective osmoprotectants in cleavage-stage embryos (such as betaine and proline) did not. At physiological osmolarities, each of these compounds resulted in significantly larger blastocysts. This was not due to increased cell numbers, which were unaffected in blastocysts by osmolarity in the range where blastocyst size was rescued by potential organic osmolytes, although cell number was decreased at higher osmolarities and was rescued by each osmolyte. The effective osmolytes were accumulated intracellularly by embryos developing in vitro from the 8-cell stage to blastocysts. However, unlike conventional organic osmolytes in somatic cells or those in cleavage-stage embryos, their intracellular concentrations were not increased with increasing external osmolarity. With the exception of beta-alanine, which is taken up via the beta-amino acid transport system, the effective osmolytes were transported by the B(0,+) system, which becomes highly active in blastocysts. The intracellular accumulation of these osmolytes in postcompaction embryos thus appears to support optimal development and blastocyst expansion at physiological osmolarities and may contribute to the embryo's ability to withstand stress.

The objective of this study was to investigate whether hypertonic hyperosmolar primes solution (HHPS), with an osmolarity of 2300 mOsmol/L, causes endothelial damage/loss. The bodies' normal osmolarity is -280 mOsmol/L. Aortic endothelial cells were cultured and plated to confluence, confirmed by light microscopy, on a 96-well plate. Serial dilutions of HHPS (n = 10) were incubated with the cells (n = 160) for 1 hour. The plates were agitated to simulate flow that occurs during cardiopulmonary bypass (CPB). One half the cells (n = 80) were stained with crystal violet to provide a visual analogue of cell survival. The second half of the cells had the HHPS removed and replaced with culture medium and were incubated overnight before being stained with crystal violet. Optical densities were measured using an optical plate reader set at 470 nm. Analysis of the endothelium after 1 hour showed that HHPS (2300 mOsmol/L) and water (positive control for 100% cell death) resulted in equal cell death, which was significantly higher (p < .05) than any of the other osmolarities tested for. There was no significant difference in the endothelial death rates for osmolarities between 260 and 400 mOsmol/L. Results of overnight incubation showed that cells in contact with a solution of osmolarity >320 mOsmol/L resulted in a significantly greater endothelial cell death rate (p < .05). Our results indicate that the endothelium can be irreversibly damaged by HHPS with osmolarities >320 mOsmol/L. The experimental protocol showed that this endothelial damage, which obviously occurs at the time of contact with the HHPS, may only become manifest 24 hours later.

The damaging effects of hypertonic stress on cellular proteins are poorly defined, and almost nothing is known about the pathways that detect and repair hypertonicity-induced protein damage. To begin addressing these problems, we screened approximately 19,000 Caenorhabditis elegans genes by RNA interference (RNAi) feeding and identified 40 that are essential for survival during acute hypertonic stress. Half (20 of 40) of these genes encode proteins that function to detect, transport, and degrade damaged proteins, including components of the ubiquitin-proteasome system, endosomal sorting complexes, and lysosomes. High-molecular-weight ubiquitin conjugates increase during hypertonic stress, suggesting a global change in the ubiquitinylation state of endogenous proteins. Using a polyglutamine-containing fluorescent reporter, we demonstrate that cell shrinkage induces rapid protein aggregation in vivo and that many of the genes that are essential for survival during hypertonic stress function to prevent accumulation of aggregated proteins. High levels of urea, a strong protein denaturant, do not cause aggregation, suggesting that factors such as macromolecular crowding also contribute to protein aggregate formation during cell shrinkage. Acclimation of C. elegans to mild hypertonicity dramatically increases the osmotic threshold for protein aggregation, demonstrating that protein aggregation-inhibiting pathways are activated by osmotic stress. Our studies demonstrate that hypertonic stress induces protein damage in vivo and that detection and degradation of damaged proteins are essential mechanisms for survival under hypertonic conditions.

Hypertonic sodium phosphate enemas are available for relief of constipation. They are widely used as colorectal laxatives because of their efficacy and because most patients tolerate the preparation well. Nevertheless, their use has been associated with decreases in intravascular volume as well as measurable changes in serum phosphorus and calcium levels. Usually these effects are transient and cause no ill effects. Severe toxicity may occur when the osmotically active hypertonic phosphate enema is retained or when it is administered to a patient with a decreased glomerular filtration rate. We report an elderly patient with previously normal renal function who developed severe hyperphosphatemia, hypocalcemia, and cardiac arrest after the administration of hypertonic sodium phosphate enemas for the treatment of an ileus. We review the patient characteristics that increase the risk of adverse effects from hypertonic sodium phosphate enemas and emphasize the danger that moderate dehydration poses when considering the use of these cathartics.

Background: Administration of a small volume of hypertonic solution has been used as an effective treatment for patients with intradialytic hypotension. Hypertonic solutions have been considered to act as plasma volume expanders. This clinical study examines whether arginine vasopressin (AVP) is involved in this mechanism of blood pressure control., Study Design: Nonrandomized trial., Setting & Participants: 42 patients on long-term hemodialysis therapy at a single hospital., Intervention: Effects of intravenous infusions of 20 mL of 10% saline, 20 mL of 50% glucose, 200 mL of 0.9% saline, or physiological doses of AVP were examined during intradialytic hypotension., Outcomes & Measurements: Changes in plasma AVP levels, osmolality, plasma volume, and blood pressure were analyzed., Results: Hypertonic saline infusion increased plasma osmolality (mean, 292.7 to 302.3 mOsm/kg H(2)O; P < 0.001), plasma AVP levels (3.9 to 7.8 pg/mL; P = 0.03), and mean arterial pressure (66.6 to 71.8 mm Hg; P = 0.01). The increase in plasma volume (2.3%; P = 0.03) was too small to increase blood pressure because of volume alone. Hypertonic glucose infusion yielded similar results. Isotonic saline infusion increased blood pressure with an abrupt increase in plasma volume (12.7%; P < 0.001). AVP infusion increased blood pressure and plasma AVP to levels similar to those induced by the hypertonic solutions., Limitations: There are limitations in accurately measuring changes in plasma volume during hemodialysis., Conclusions: Results strongly suggest that the osmotic stimulation of AVP secretion by hypertonic solutions has an important role in increasing blood pressure in patients with intradialytic hypotension. Manipulating plasma AVP appropriately may help correct and prevent intradialytic hypotension.

Blood brain barrier disruption enhances drug delivery in primary central nervous system lymphoma. In this study, we report adverse events that were encountered intraoperatively and in the postoperative period in these patients. A retrospective analysis of 17 patients documenting demographic data, preprocedure medical history, intraoperative, and postoperative anesthetic complications was conducted between January 2002 and December 2004. Seventeen patients underwent 210 treatments under general anesthesia with a mean of 12.4+/-7.2 treatments per patient. Focal seizures occurred in 13% of patients. Generalized motor seizures occurred in 4 treatment sessions in 2 different patients. The incidence of seizures was significantly higher when the internal carotid artery was used for injection, as opposed to the vertebral artery (20.8% and 6.02%, respectively, P=0.0034). Tachycardia associated with ST segment depression occurred 9 times (4.3%) in 3 patients. One patient had significant ST segment elevation (more than 1.5 mm). Transient cerebral vasospasm after methotrexate injection occurred in 9% of patients. Postoperative nausea and vomiting were observed in 11.9% of patients. After emergence, lethargy and obtundation occurred in 7.6% of the cases. The incidence of postoperative headache and reversible motor deficits was 6% and 3.8%, respectively. Our review highlights the problems that were encountered during blood brain barrier disruption under anesthesia and in the postoperative period. Further prospective studies are required for comprehensive evaluation of intraprocedure and postprocedure complications that will allow development of an optimal anesthetic plan and will improve patient outcome by preventing potential complications.

We report a 31-year-old woman scheduled for a right frontal craniotomy and debulking of a recurrent grade 3 astrocytoma. Mannitol was given at the request of the surgeons. Peaked T waves were noted on electrocardiography, and electrolyte analysis showed hyperkalemia and hyponatremia.

The purpose of this study was to examine the relationship between osmolality and efferent sympathetic outflow in humans. We hypothesized that increased plasma osmolality would be associated with increases in directly measured sympathetic outflow. Muscle sympathetic outflow was successfully recorded in eight healthy subjects during a 60-min intravenous hypertonic saline infusion (HSI; 3% NaCl) on one day and during a 60-min intravenous isotonic saline (ISO) infusion (0.9% NaCl) on a different day. The HSI provides an osmotic and volume stimulus, whereas the ISO infusion provides a volume-only stimulus. Muscle sympathetic nerve activity was quantified using the technique of peroneal microneurography. Plasma osmolality increased during the HSI but not during the ISO infusion (ANOVA, P < 0.05). Sympathetic outflow differed between the trials (ANOVA, P < 0.05); during the HSI burst, frequency initially increased from 14.6 +/- 2.5 to 18.1 +/- 1.9 bursts/min; during the ISO infusion, burst frequency initially declined from 14.7 +/- 2.5 to 12.0 +/- 2.1 bursts/min. Plasma norepinephrine concentration was greater at the end of the HSI compared with the end of the ISO infusion (HSI: 297 +/- 64 vs. ISO: 202 +/- 49 pg/ml; ANOVA, P < 0.05). We conclude that HSI-induced increases in plasma osmolality are associated with increases in sympathetic activity in humans.

Background: Adult-onset type II citrullinemia (CTLN2) is an autosomal recessive disorder caused by mutations of SLC25A13 gene encoding citrin and is characterized by recurrent encephalopathy with hyperammonemia. Factors affecting disease progression remain unknown. We report a case with CTLN2, whose clinical course was rapidly worsened by the administration of Glyceol, a hyperosmotic diuretic solution consisting of 10% glycerol and 5% fructose in saline., Case Report: A 34-year-old man was admitted in coma after repeated episodes of altered consciousness. His plasma ammonia level was markedly elevated without any evidence of liver diseases. Brain MRI revealed high signal intensities at the bilateral cingulate gyri and insular cortices, suggesting hepatic encephalopathy. We administered Glyceol. intravenously to alleviate brain edema, however, he developed intractable seizures along with steep increase in plasma ammonia levels (from 808 to 2210 microg/dL) and died. The diagnosis of CTLN2 was confirmed by elevations of plasma citrulline level (384.3 nmol/mL; normal 17-43 nmol/mL) and serum pancreatic secretory trypsin inhibitor (PSTI) (110 ng/mL; normal 4.6-12.2 ng/mL), decrease in hepatic argininosuccinate synthetase activity (5.5% of control), lack of hepatic citrin protein expression and mutations in SLC25A13 gene (compound heterozygote with S225X and Ex1-1G>A)., Conclusions: Physicians should take CTLN2 into consideration as a differential diagnosis in Asian patients with a history of repeated unconsciousness with hyperammonemia and use D-mannitol but not glycerol to treat brain edema in patients with CTLN2.

Introduction: When low doses of local anesthetic are used in combined spinal-epidural anesthesia for cesarean section, an epidural catheter can be used to enhance a possibly incomplete block or insufficient dose., Objective: To compare the efficacy of spinal 0.5% hyperbaric bupivacaine with fentanyl (20 microg) at a conventional high dose of 0.07 mg cm(-1) (group 1) vs 0.25% levobupivacaine at a low dose of 7.6 mg with fentanyl (20 microg) and epidural volume extension with 6 mL of saline through an epidural catheter (group 2)., Material and Methods: A randomized clinical trial enrolling patients scheduled for elective cesarean section., Results: Sixty-two patients were studied (31 in each group). Characteristics in the groups were comparable at baseline and the maximum level of sensory block achieved was sufficient for all but 1 patient in group 2 who required general anesthesia. The bupivacaine dose in group 1 ranged from 10.5 to 12 mg. The motor block and duration was less intense in group 2 (P<0.0001) and patients in that group could be transferred out of the postanesthetic care unit earlier., Conclusions: The use of low doses of levobupivacaine with an opiate in combination with volume extension through an epidural catheter in the context of combined spinal-epidural anesthesia is a safe, effective technique that may allow the doses and motor block to be reduced when hyperbaric levobupivacaine is administered, without adverse events for patients.

Background: Toxicity secondary to rectally administered hypertonic phosphate solution in patients with normal renal function is rarely reported in the literature. We report a case of electrolyte disturbance and seizure secondary to the rectal administration of 2 Fleet pediatric enemas., Case Report: A 4-year-old white female with spinal muscular atrophy and chronic constipation was brought to the emergency department with complaints of lethargy and difficulty breathing following the administration of 2 Fleet pediatric enemas. In the emergency department, physical examination was significant for a depressed level of consciousness and shallow respirations. A basic metabolic profile was significant for a calcium of 3.3 mg/dL, phosphate of 23 mg/dL, and sodium of 153 mEq/L. Arterial blood gases revealed a pH of 7.24, Pco2 of 38 mm Hg, Po2 of 220 mm Hg. Electrocardiogram revealed a prolonged QT interval of 340 milliseconds with a corrected QT interval of 498 milliseconds. Sixteen hours postexposure, she experienced a generalized seizure unresponsive to multiple doses of lorazepam and responsive only to 100 mg of intravenous calcium chloride. Two days after presentation, the patient experienced complete resolution of symptoms., Conclusion: Osmotically acting hypertonic phosphate enemas can result in severe toxicity if retained. This is true even in patients without predisposing risk factors.

Osp94 (osmotic stress protein of 94 kDa) is known to be up-regulated by hypertonic and heat-shock stresses in mouse renal inner medullary collecting duct (mIMCD3) cells. To investigate the molecular mechanism of transcriptional regulation of the Osp94 gene under these stresses, we cloned and characterized the 5'-flanking region of the gene. Sequence analysis of the proximal 4 kb 5'-flanking region revealed a TATA-less G/C-rich promoter region containing a cluster of Sp1 sites. We also identified upstream sequence motifs similar to the consensus TonE/ORE (tonicity-response element/osmotic response element) as well as the consensus HSE (heat-shock element). Luciferase activities in cells transfected with reporter constructs containing a TonE/ORE-like element (Osp94-TonE; 5'-TGGAAAGGACCAG-3') and HSE enhanced reporter gene expression under hypertonic stress and heat-shock stress respectively. Electrophoretic gel mobility-shift assay showed a slowly migrating band binding to the Osp94-TonE probe, probably representing binding of TonEBP (TonE binding protein) to this enhancer element. Furthermore, treatment of mIMCD3 cells with MAPK (mitogen-activated protein kinase) inhibitors (SB203580, PD98059, U0126 and SP600125) and a proteasome inhibitor (MG132) suppressed the increase in Osp94 gene expression caused by hypertonic NaCl. These results indicate that the 5'-flanking region of Osp94 gene contains a hypertonicity sensitive cis -acting element, Osp94-TonE, which is distinct from a functional HSE. Furthermore, the MAPK and proteasome systems appear to be, at least in part, involved in hypertonic-stressmediated regulation of Osp94 through Osp94-TonE.

We have developed a novel device for the quantification of edematous morphology changes in acute brain slices. We can also carry out real-time monitoring of detailed hippocampal cells. The device we developed is based on infrared differential interference contrast microscopy (IR-DIC) and a custom-made real-time computerized image-analysis system for quantification of the morphological dynamics of cells in slice preparations. We applied the coefficient of variation (CV) of light intensity in IR-DIC images to evaluate the change in morphological dynamics. We examined three kinds of edema in the CA1 region of rat hippocampal acute slices under conditions of hypotonic, strong excitation, and experimental ischemia, together with field excitatory postsynaptic potential (fEPSP) recording from radiatum in CA1 the region. There were notable close relationships among the edema formations, the light transmittance, the extent of changes in CV, and features of fEPSP during the three different insults. The present results indicate that CV is a reliable quantification index for edema formation in brain tissue and confirm that applying CV for the analysis in addition to the light transmittance analysis presents additional important information on brain tissue swelling., (Copyright 2004 Wiley-Liss, Inc.)

Unlabelled: Sclerosing encapsulating peritonitis secondary to peritoneal dialysis has been associated to acetate-containing dialysis fluids, hypertonic glucose and disinfectants. Physiopathologic mechanisms of fibrotic proliferation that implicate those agents are not totally explained. With an experimental approach using cultured peritoneal fibroblasts, we have studied intracellular pH changes and Na+/H+ antiporter activity under cells perfusion with peritoneal dialysis liquids containing acetate, lactate, hypertonic glucose and interleukin-1. All experiments were performed at extracellular pH 7.4 and physiologic HCO3/CO2 concentration., Results: 35 mM acetate produced a huge intracellular acidosis (ipH = 6.80 +/- 0.08). Lactate effect was less important (6.95 +/- 0.07), with a slow ipH recovery in about 30 min in both cases. IL-1, 10(-6) M also reduced ipH to 7.10 +/- 0.03. Acidosis was linked to Ca2+ outflow via Ca/H exchange and was blocked with Cd 20 nM. Extracellular Na = 0 and amiloride totally inhibited ipH recovery after acetate, lactate, or interleukin-induced acidosis. Hypertonic glucose perfusion increased ipH (7.31 +/- 0.06) for 5-7 min. This increase was also inhibited by amiloride or extracellular Na absence. Na+/H+ exchanger activity increased to 58%, and kept activated after ipH recovery. In conclusion, acetate, hypertonic glucose and IL-1 showed the common effect of stimulating the sodium-proton exchanger by different mechanisms, giving a possibility of potentiation. Activated Na+/H+ exchanger may act as a signal-transduction increasing fibroblast proliferation and explaining the cellular mechanism of sclerosing peritonitis.

Objective: To determine whether Belzer solution (Viaspan, Bristol-Myers Squibb, Brussels, Belgium), which is more expensive than Eurocollins solution, was better at preventing delayed graft function (DGF) and whether it was cost-effective as it could potentially reduce post-transplantation complications., Method: The risk of occurrence of complications associated with the use of these two rinsing and preserving solutions was estimated from a survey of 106 patients undergoing renal transplantation between 1 January 1993 and 31 March 1998. Both efficacy and adverse outcomes were recorded along with the costs directly associated with the transplantation procedure in the hospital setting: hospitalization, rinsing and preserving solutions, medical and technical interventions and diagnostic tests., Results: For the 45 kidney grafts rinsed and preserved with Eurocollins (strategy S1: n1 = 45) the cost/graft was estimated at 40 euros. With Viaspan (strategy S2: n2 = 61) the corresponding cost/graft was 424 euros. Logistic regression analysis showed that Viaspan was better than Eurocollins solution (ebeta = 0.437; P = 0.05) in preventing DGF. Overall, S2 was less expensive than S1, from the hospital's perspective. The mean difference per patient was 278 euros, which amounts to a saving of 2% of the total cost per renal transplantation. For rinsing and preserving kidney grafts Belzer solution is therefore preferable to Eurocollins solution.

Background: Hypertonic solutions are useful for the management of hypovolemic shock but cause impairment in platelet function. This effect would reduce the ischemia/reperfusion damage caused by activated platelets, but it could be the cause of aggravating blood loss in case of uncontrolled hemorrhage. In this paper, it was studied if osmotic shrinkage of platelets affects the changes in intracellular calcium concentration ([Ca(2+)](i)) induced by thrombin or adenosine 5' diphosphate (ADP). Furthermore, it was investigated if hypertonic solutions change the mobilization from intracellular stores or the calcium entry. Previous reports from our laboratory described that the capacitative calcium entry is increased by alkalization and also that hyperosmolarity has an alkalinizing effect on human platelets so it was hypothesized that hyperosmolarity would be able to modify agonist-induced calcium entry., Material and Methods: To study the response to agonists, platelets loaded with 2'7'-bis(carboxyethyl)-5(6)-carboxy-fluorescein (FURA 2) were incubated at 37 degrees C for 500 s in a N-2-hidroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES)-buffered solution with 1 mM CaCl(2). The osmolarity of the solution was elevated by the addition of 200 mM mannitol or sucrose and after the stimulation with 0.1 IU/ml of thrombin or 100 microM ADP, [Ca(2+)](i) increases were compared. Platelets incubated in zero calcium/EGTA were stimulated with these agonists or with 0.1 microM thapsigargin to separately study the effect of hyperosmolarity on both calcium mobilization from intracellular stores and extracellular calcium entry., Results: It was found that hypertonic solutions decrease the [Ca(2+)](i) peak induced by the agonist: The increase of [Ca(2+)](i) in the presence of 200 mM mannitol produced by 100 microM ADP was 62+/-6% and response to 0.1 IU/ml thrombin was 74+/-7% of the increase in isotonic control solution. In the case of ADP, both mobilization and calcium entry were reduced to 66+/-3% and 65+/-6% of isotonic control, respectively. In the case of thrombin, only the mobilization showed a significant change (79+/-2% of parallel control). In platelets depleted by thapsigargin, the capacitative calcium entry was increased in hypertonic mannitol (174+/-25% of the isotonic control). Similar results were obtained with hypertonic sucrose solutions., Conclusions: In spite of the stimulatory effect of hyperosmolarity on capacitative calcium entry observed in platelets in which the calcium stores were depleted with thapsigargin, the full response of intracellular calcium to the agonists tested (ADP and thrombin) was reduced by an increase in osmolarity. The decreased Ca(2+) mobilization observed may play a role in the reduction in hypertonic media of accompanying platelets responses such as aggregation or shape change.

Background: Cold ischemia and reperfusion during kidney transplantation are associated with release of free oxygen radicals and damage of renal tubular cells. Bioflavonoids may diminish cold storage-induced injury due to antioxidant and iron chelating activities. This study was designed to delineate the renoprotective mechanisms of bioflavonoids and to define the structural features conferring cytoprotection from cold injury., Methods: LLC-PK1 cells were preincubated for three hours with bioflavonoids and cold stored in University of Wisconsin (UW)- or Euro-Collins (EC)-solution for 20 hours. After rewarming, cell viability was assessed by the lactate dehydrogenase (LDH) release, MTT-test, and amino acid transport activity. Lipid peroxidation was assessed from the generation of thiobarbituric acid-reactive substances., Results: Twenty-hours of cold storage of LLC-PK1 cells resulted in a substantial loss of cell integrity that was more pronounced in the EC (LDH release, 93.6 +/- 1.6%) than the UW solution (67.2 +/- 6.9%; P < 0.0001). Pretreatment with quercetin significantly enhanced cell survival (LDH release, 5.4 +/- 2.7% for UW and 8.4 +/- 4.2% for EC) in a concentration dependent manner. Structure-activity studies revealed similar renoprotection for kaempferol, luteolin and fisetin, unlike myricetin, morin, apigenin, naringenin, catechin, silibinin and rutin. Lipid peroxidation was reduced (UW alone, 2.7 +/- 1.2 vs. UW+quercetin 0.5 +/- 0.2 nmol/mg protein, P < 0.01), and l-threonine uptake completely sustained by pretreatment with quercetin, kaempferol, luteolin, and fisetin. However, renoprotection by fisetin was rapidly lost during rewarming. Protective properties of bioflavonoids were governed by the number and arrangement of hydroxyl substitutes, electron-delocalization, sterical planarity, and lipophilicity of the basic diphenylpyran skeleton., Conclusion: Cold storage-induced renal tubular cell injury is ameliorated by bioflavonoids. Renoprotective effects of bioflavonoids are defined by structure, suggesting that flavonoids are incorporated into membrane lipid bilayers and interfere with membrane lipid peroxidation.

Oxygen metabolites play an important role in renal injury during myoglobinuric acute renal failure (ARF). This study was designed to determine the protective influence of N-acetylcysteine (NAC), a hydroxyl radical scavenger, and treatment in an experimental model of myoglobinuric-ARF induced by intramuscular injection of hypertonic glycerol in rats. The rats were randomly distributed into five groups: Group 0 (n = 10), was assigned to receive 2mL saline (0,9%) intraperitoneally (ip); Group 1 (n = 10), NAC ip in a dose of 0 mg/100 g of body weight 30 min before the intramuscular (im) injection of 50% glycerol (10 mg/kg); Group 2 (n = 10), received saline 0,9% ip in a equivalent volume of NAC in Group I before the im injection of glycerol; Group 3 (n = 10), received NAC ip in a dose of 10 mg/100 g after im injection of glycerol; Group 4 (n = 10), saline 0,9% ip in a equivalent volume of NAC of the Group 3 after im administration of glycerol. After 24 h rats were sacrificed and kidney morphology and renal function were determined. A severe renal failure was produced by glycerol injection in the Groups 1, 2, 3, and 4, with significant tubular proximal necrosis and cast formation, and creatinine and urea concentrations were elevated in these groups without significant differences among groups, but Group 0 where the values were significantly lower. The results of this study suggests that ip administration of NAC in rats before or after glycerol injection do not confer protection against impairment of renal function under these conditions in this model of myoglobinuric-ARF.

Resuscitation with hypertonic saline (HS) appears to aggravate bleeding in a model of uncontrolled hemorrhage [J. Trauma 28 (1988) 751; J. Trauma 29 (1989) 79; Arch. Surg. 127 (1992) 93]. This property may be related to the anticoagulant effects of HS on plasma clotting factors and platelets [J. Trauma 31 (1991) 8]. The hypothesis in this study is that a hypertonic solution can be developed that would not disturb the blood coagulation mechanism and could be used as an alternative to hypertonic saline.HS and four different 2400 mosM solutions containing monosaccharides and/or glycine were screened for their in vitro effects on plasma clotting times and platelets. Significant prolongations falling outside the normal range were detected in prothrombin time (PT) and thrombin rime (TT) when only 5% of the volume of normal plasma is HS. Platelet function as measured by extent of shape change (ESC) induced by ADP and aggregation induced by thrombin were also critically impaired by HS at a 5% dilution. All alternative solutions-hypertonic glucose, sorbitol, glycine, glucose/glycine, glucose/mannitol/glycine, sorbitol/glycine-caused a significantly reduced impairment in platelet function and the plasma coagulation system. Hypertonic glycine showed a unique ability to fully preserve the function and integrity of the plasma coagulation system. Considering the pre-deposition of the trauma patient to coagulopathy, administration of HS which clearly is a potent anticoagulant and anti-platelet risks further aggravating the coagulopathy. In contrast, hypertonic glycine preserves the blood coagulation mechanism and exhibits the potential for numerous therapeutic applications. Therefore, prompt evaluation of hypertonic glycine as a resuscitative fluid is highly desirable.

Objective: Chronic peritoneal dialysis (PD) may eventually result in vascular alterations of varying degree, which lead to progressive reduction in dialytic efficacy. Although the pathogenesis has not been elucidated yet, vascular endothelial growth factor (VEGF) has been proposed to play a central role in the process leading to vascular alterations., Design: Rats were allocated to three groups: no treatment, intraperitoneal introduction of hypertonic PD solution alone, and intraperitoneal introduction of hypertonic PD solution plus octreotide. After 4 weeks, a 1-hour peritoneal equilibration test (PET) was performed. Dialysate-to-plasma urea ratio (D/P urea), glucose reabsorption (D1/D0 glucose), ultrafiltration volume (UF), and levels of dialysate protein and VEGF were determined. Peritoneal membrane histology was evaluated by light microscopy., Results: Compared with the control group, rats treated with hypertonic PD solution showed dramatically deranged peritoneal function tests (UF: 5.8 +/- 0.9 mL vs 1.3 +/- 0.6 mL; D/P urea: 0.49 +/- 0.1 vs 0.74 +/- 0.04; D1/D0 glucose: 0.55 +/- 0.05 vs 0.34 +/- 0.06) and morphology (thickness: 4.6 +/- 0.4 mu vs 62 +/- 12 mu; neovascularisation: 0.1 +/- 0.3 vessels per field vs 2.2 +/- 0.3 vessels per field). Similarly, a higher level of VEGF was found in the rats treated with hypertonic PD solution. In rats treated with hypertonic solution plus octreotide, peritoneal thickness was not completely reduced (25 +/- 5 mu), but peritoneal functions were protected (UF: 4.0 +/- 0.5 mL; D/P urea: 0.58 +/- 0.02; D1/D0 glucose: 0.51 +/- 0.02). Moreover, VEGF level and neoangiogenesis were significantly less in the octreotide group than in the group treated with hypertonic dextrose alone., Conclusion: Our data document that, by increasing the production of VEGF, a high glucose concentration can cause vascular alterations within the peritoneal membrane. Octreotide can protect against the vascular alterations and preserve peritoneal function by inhibiting overexpression of VEGF and regulating the inflammatory response in the peritoneum.

Peritoneal equilibration test (PET) employing a 2.27%/2.5% glucose exchange is the most widely used method of to evaluating peritoneal function and small solute transport. Hypertonic (3.86%/4.25% glucose) PET has been recently recommended for the evaluation of ultrafiltration and to study certain causes of ultrafiltration failure, such as aquaporin dysfunction, through the analysis of dialysate sodium. However, there is not enough information on the optimal way to express the changes in dialysate sodium concentration, the normal range of values for this parameter, and possible adverse effects of hypertonic PET in the general population of peritoneal dialysis patients. A hypertonic PET was performed in 22 patients. Ultrafiltration failure (ultrafiltration < 0.4 L) was present in seven patients. Patients with ultrafiltration failure had higher small solute peritoneal transport and dialysate sodium concentration and had been treated with peritoneal dialysis for longer periods of time. Dialysate sodium concentration at 60 and 240 minutes was directly correlated with small solute peritoneal transport calculated as D/PCr240 (r = 0.74, p = 0.0008 y r = 0.84, p < 0.0001) and inversely correlated with ultrafiltration (r = 0.64, p = 0.0016 y r = 0.72, p = 0.0002). An absence of a dip in dialysis sodium, suggestive of aquaporin dysfunction, was only observed in one patient with a high-average small solute peritoneal transport. Dialysate sodium concentration at 60 minutes is a better discriminator between ultrafiltration failure patients than parameters such as D/PNa or the absolute dip in dialysate sodium with respect to time zero. We observed the following adverse effects: symptomatic hypotension in 2 patients with preserved ultrafiltration. In conclusion, hypertonic PET allows to confirm the diagnosis of ultrafiltration failure, but monitoring dialysate sodium concentration offers additional information only in patients with severe aquaporin dysfunction. Hypertonic PET may have adverse effects in patients without ultrafiltration failure.

Objective: Peritoneal fibrosis (PF) is one of the most serious causes of failure in continuous ambulatory peritoneal dialysis (PD). Although the underlying mechanism responsible for the genesis of PF is still unknown, transforming growth factor beta (TGFbeta1) has been shown to be associated with PF. Angiotensin converting enzyme inhibitors have been shown to prevent the stimulating effect of growth factors. The aim of the present study was to investigate the effect of enalapril on peritoneal function and morphology in a rat model of experimental PF., Methods: Twenty-one albino Wistar rats were divided into three groups: (1) the control group (C) received 10 mL isotonic saline intraperitoneally (i.p.), (2) the dextrose (Dx) group 10 mL 3.86% dextrose PD solution i.p., and (3) the enalapril-treated group (ENA) 10 cc 3.86% dextrose PD solution i.p. plus 100 mg/L enalapril in drinking water. After 4 weeks, a 1-hour peritoneal equilibration test was performed with 20 mL 2.27% dextrose PD solution. Dialysate-to-plasma urea ratio (D/P urea), glucose reabsorption (D1/D0 glucose), ultrafiltration (UF) volume, and levels of dialysate protein, TGFbeta1, and cancer antigen 125 (CA125) were determined. The parietal peritoneum was evaluated histologically by light microscopy., Results: Administration of enalapril resulted in preserved UF (-0.2 +/- 0.7 mL vs 1.7 +/- 0.3 mL, p < 0.05), protein loss (2.3 +/- 0.5 g/L vs 1.6 +/- 0.2 g/L, p > 0.05), and peritoneal thickness (77 +/- 7 microns vs 38 +/- 5 microns, p < 0.001). D/P urea increased significantly in the Dx group (p< 0.05). Both higher levels of TGFbeta1 (undetectable vs 298 +/- 43 pg/mL, p < 0.001) and lower levels of CA125 in dialysate effluent (0.94 +/- 0.5 U/L vs 0.11 +/- 0.1 U/L, p > 0.05) were determined in the Dx group., Conclusion: These findings show that peritoneal morphology and function tests were dramatically deranged in the Dx group. The same properties were partially preserved in the ENA group. The production of TGFbeta1 was significantly reduced but peritoneal thickness was not completely inhibited. In conclusion, by inhibiting the production of TGFbeta1, enalapril can preserve peritoneal histology, peritoneal function, and remodeling of mesothelial cells.

Physical and chemical irritation of the peritoneum through glucose-based hyperosmolar dialysis solutions results in a nonbacterial serositis with fibrinous exudation. Thereby, human peritoneal mesothelial cells (HMC) play an important role in maintaining the balance between the peritoneal generation and degradation of fibrin by expressing the fibrinolytic enzyme tissue-type plasminogen activator (t-PA) as well as the specific plasminogen activator inhibitor-1 (PAI-1). In this study, we analyzed the effect of D-glucose and metabolically inert monosaccharides on the synthesis of t-PA and PAI-1 in cultured HMC. Incubation of HMC with D-glucose or the metabolically inert monosaccharides mannitol and L-glucose (5-90 mM) resulted in a time- and concentration-dependent increase in t-PA mRNA expression and antigen secretion without affecting PAI-1 synthesis. A similar effect was evident when HMC were first exposed sequentially to pooled spent peritoneal dialysis effluent for up to 4 hours, and subsequently incubated for 20 hours in control medium. The stimulating effect of high D-glucose on t-PA expression in HMC was prevented by treating the cells with different protein kinase C (PKC) inhibitors (Ro 31-8220, Gö 6976), but could not be mimicked by the PKC-activating phorbol ester PMA, indicating that this effect of high glucose is dependent on PKC activity, but not mediated through PKC activation. Also, using specific inhibitors (PD 98059, SB 203580) and activators (PMA, anisomycin, IL-1alpha) of the major routes of the mitogen-activated protein kinases (MAPKs) cascade, we found no evidence for a role of this cascade in regulating t-PA expression in HMC. We conclude that hyperosmolarity induces t-PA (but not PAI-1) in HMC via a regulatory mechanism that requires active PKC, but that does not involve a major pathway in the MAPK cascade.

Hypertonic-hyperoncotic solutions are a supplementary possibility in the acute treatment of hypovolemia. The main mechanism of action of this solution is, induced by the tonicity of the infusion (approximately 2400 mOsm/l), the transcapillary fluid shift from the intracellular and interstitial to the intravascular compartment. Additionally the fluidity of blood is improved (due to an increase in the diameter of the capillaries), the adherence of leucocytes to the endothelial wall is reduced, and the arteriolar vasomotion is restarted. Due to the available prehospital and clinical results it can be concluded, that hypertonic-hyperoncotic solutions offer advantages compared to conventional fluid therapy regimes: rapid stabilization of hemodynamics, reduction of posttraumatic volume deficiency, of posttraumatic edema and of posttraumatic complications and an improvement of the outcome of the patients. If the therapeutic recommendations are followed, such as a dose of 4 ml/kg body weight, infusion time of about 3-5 minutes and after the end of the infusion application of colloids or crystalloids in an amount as needed, no side effects will occur. Only immediately after the end of infusion sodium, chloride and osmolarity will slightly increase, however these parameters will normalize within the first posttraumatic day. Hypertonic-hyperoncotic solutions are trigger-solutions, as with the infusion of these types of solution it is possible to restore hemodynamics adequately and to prevent shock-induced complications.

Objective and Importance: We report a case of head injury, in which a hyperosmolar state evolved during the course of treatment, complicated by severe rhabdomyolysis and acute renal failure, which subsequently resulted in a good recovery after intensive supportive treatment. To our knowledge, such high levels of creatine kinase in a patient with head injury and rhabdomyolysis have not been reported., Clinical Presentation and Intervention: A 19-year-old male patient with head injury sustained a compound fracture of the frontal region. He received a hyperosmolar agent to treat brain edema and developed a hyperosmolar state and diabetes insipidus 1 day after the accident. There were no obvious associated injuries at physical examination. After admission to the intensive care unit, the patient developed myoglobinuria and rhabdomyolysis; serum creatine kinase was elevated to a peak of 650,000 IU/L. Four days later, acute renal failure was noted. The patient's myoglobinuria and rhabdomyolysis gradually declined, and he eventually recovered from acute renal failure after supportive treatment and dialysis., Conclusion: We postulate that the hyperosmolar state of the patient was the major cause of his severe rhabdomyolysis. Associated hypokalemia and hypophosphatemia are also predisposed to rhabdomyolysis. The most serious complication in rhabdomyolysis is acute renal failure, but most patients who receive supportive treatment and can survive despite the complications can expect to have normal renal function restored.

We found that Dictyostelium amebas shrank about 50% in 10 min after a change in extracellular osmolarity from 70 mosM to 170-370 mosM. Cells shrunk by the addition of 0.1 M mannitol showed a partial recovery of cell volume in 2 h when the culture medium contained salts. A full recovery of cell volume was observed when 0.1 or 0.2 osM NaCl or KCl was added instead of mannitol. No recovery of cell volume was observed after the addition of 0.1 M mannitol or glycine when the extracellular medium did not contain any salt. An elevation in extracellular pH of starved Dictyostelium cells, which is probably due to ammonia production, was suppressed by hypertonic stress. This hypertonic stress-induced suppression of the elevation in extracellular pH was observed only when the extracellular medium contained salt. We also found that cells with artificially elevated intracellular pH withstood hypertonic stress much better than control cells. These results suggest that Dictyostelium cells under hypertonic conditions secrete protons and take up charged extracellular osmolytes in exchange. The uptake of charged osmolytes induces the elevation of intracellular osmotic strength and the recovery of cell volume. The elevation of intracellular pH, which is presumably induced by the proton secretion, plays a role in protecting cells from lysis.

Background: Previous reports have suggested that sequential applications of sodium fluorescein (NaF) to the ocular surface cause loss of epithelial cells. In those experiments the solutions were free of preservatives, but delivered a hypertonic and alkaline load. It is possible that either the hyperosmolarity, NaF, and/or alkalinity may have contributed to the epithelial cell loss. Our study explored the possible impact of these three factors on epithelial integrity., Methods: We used a paradigm in which we designed four test solutions to isolate the cytotoxic effects of the three factors. Fifteen subjects were exposed to one of the solutions on separate visits. One solution was instilled in both eyes, every 3 min, for a total of seven applications, and a slitlamp examination was performed. Staining was graded on a scale of 0 to 3 for each of five corneal sectors., Results: Application of solution 1 (NaF, hyperosmotic, and alkaline) resulted in staining for all subjects. For the other three solutions (without NaF), insignificant staining occurred., Conclusions: The epithelium tolerates changes in pH and osmolarity between 7.2 to 7.8 and 290 to 350, respectively. However, NaF when applied in multiple doses may be cytotoxic.

A largely positive perioperative fluid balance during both elective and emergency abdominal aortic aneurysm repair (AAA) may put patients at risk of developing left ventricular failure and may thus contribute to morbidity. In the present paper we report on a prospective study using hyperosmotic-hyperonocotic solutions (HHS) infused during clamping of the aorta, for the prevention of declamping shock, and the associated reduction in perioperative fluid requirements. The major aim of this paper was to determine the efficacy of an HHS infusion when given over 20 minutes and to detect possible adverse effects of HHS. For perioperative fluid replacement 12 patients received crystalloid solutions with HHS [250 ml of 7.2% NaCl combined with either 6% Dextran (n = 3), 6% Hydroxyethylstarch (HES, n = 4) or 10% HES (n = 5)]. In 16 controls, crystalloids with 1000 ml of HES 10% were infused. Patients were invasively monitored and hemodynamic parameters frequently assessed during the operation, which were statistically analyzed in relation to the start of the fluid loading during clamping of the aorta. One patient showed an anaphylactoid reaction to HES, otherwise no side effects of HHS were observed during infusion (no hypotension, no pathological EKG changes). Plasma sodium and chloride concentration as well as osmolality rose resulting in an osmotic gradient and a desired intravascular volume expansion. Prior to declamping pulmonary capillary wedge pressure had increased to the desired value of > 13 mmHg and < 18 mmHg. Oxygen delivery was significantly elevated upon HHS and remained so post declamping, whereas no change was observed in controls. During clamping systemic vascular resistance was significantly decreased, but was unchanged in controls. The perioperative fluid balance of patients receiving HHS was 2471.0 +/- 948.6 ml, which was significantly less than + 3386.7 +/- 1247.9 ml of controls (P < 0.01). We suggest that HHS opens new perspectives in perioperative fluid management of both elective and emergency AAA repair, since hemodynamic parameters are improved and the overall fluid balance is less positive, thus decreasing the likelihood of edema formation. Moreover, the previously described positive microcirculatory effects of HHS may be particular beneficial in some high-risk patients.