[Is physiological saline really physiological? Hyponatreamia treatment--small deviations from the rules of appropriate therapy create serious complications and side effects]. / Czy sól fizjologiczna jest fizjologiczna? Leczenie hiponatremii--male odstepstwa od regul prawidlowego leczenia powoduja powazne powiklania i objawy uboczne.

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.

Mannitol versus hypertonic saline for brain relaxation in patients undergoing craniotomy.

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.

Early utilization of hypertonic peritoneal dialysate and subsequent risks of non-traumatic amputation among peritoneal dialysis patients: a nationwide retrospective longitudinal study.

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.

Out-of-hospital hypertonic resuscitation after traumatic hypovolemic shock: a randomized, placebo controlled trial.

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.

Rescue of postcompaction-stage mouse embryo development from hypertonicity by amino acid transporter substrates that may function as organic osmolytes.

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.

Flow-through peritoneal dialysis in neonatal enema-induced hyperphosphatemia.

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.

Comprehensive biophysical and functional study of ziv-aflibercept: characterization and forced degradation.

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 ß-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.

Role of Hypoxia in Renal Failure Caused by Nephrotoxins and Hypertonic Solutions.

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 Po2, 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.

Effect of hyperosmolality on vasopressin secretion in intradialytic hypotension: a mechanistic study.

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.

Perioperative complications of blood brain barrier disruption under general anesthesia: a retrospective review.

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.

Hypertonic cardiopulmonary bypass primes and endothelial damage.

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.

Fatal iatrogenic hyperphosphatemia.

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.

Electrolyte changes during craniotomy caused by administration of hypertonic mannitol.

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.

[Low-dose 0.25% spinal levobupivacaine with epidural extension for cesarean section: comparison with 0.5% hyperbaric bupivacaine]. / Dosis bajas de 1-bupivacaína 0,25% espinal con extensión con salino epidural para cesárea: comparación con bupivacaína 0,5% hiperbárica.

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.

Life-Threatening Mannitol-Induced Hyperkalemia in Neurosurgical Patients.

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.

Regulation of expression of the stress response gene, Osp94: identification of the tonicity response element and intracellular signalling pathways.

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.

Prehospital Resuscitation of Traumatic Hemorrhagic Shock with Hypertonic Solutions Worsens Hypocoagulation and Hyperfibrinolysis.

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.

D-glucose increases the synthesis of tissue-type plasminogen activator (t-PA) in human peritoneal 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.

Controversies in shock research: hypertonic resuscitation--pros and cons.

The proper fluid resuscitation of hemorrhagic shock is still controversial. Hypertonic saline has been suggested for prehospital resuscitation of hemorrhagic shock, because of its superior ability to expand blood volume and elevate systemic blood pressure and cardiac output in a small volume and during a short time period. We have defined two types of hemorrhagic shock: controlled hemorrhagic shock (CHS), where the bleeding source is immediately occluded following hemorrhage, and uncontrolled hemorrhagic shock (UCHS), where bleeding is induced by injury to blood vessels that are left unoccluded. It was observed that hypertonic saline (HTS) treatment of controlled hemorrhagic shock leads to an increase in blood pressure and cardiac output, while HTS treatment of UCHS leads to increased bleeding from injured blood vessels, hemodynamic deterioration, and increased mortality. Conversion of UCHS to CHS by tourniquet, military antishock trousers, or surgical hemostasis prevented excessive bleeding and mortality following HTS. Several clinical studies have used hypertonic saline dextran (HSD) or hypertonic saline (HS) for treatment of trauma casualties, but to date no significant improvement in mortality has been demonstrated by either HS or HSD. A more favorable effect but still not statistically significant effect has been demonstrated in patients with a Glasgow Coma Scale of 8 or less. The efficacy of HS has not clearly been established in clinical trials, in all of which HS was used in combination with conventional crystalloid therapy. Further human trials are required to better define the patient population that would benefit most from the prehospital administration of HS.