Design and Rationale for the Veterans Affairs "Cooperative Study Program 594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat" Trial.

BACKGROUND: Gout patients do not routinely achieve optimal outcomes related in part to suboptimal administration of urate lowering therapy (ULT) including first-line xanthine oxidase inhibitors allopurinol or febuxostat. Studies leading to the approval of febuxostat compared this agent to allopurinol in inappropriately low, fixed doses. We will compare allopurinol with febuxostat in gout using appropriately titrated doses of both agents and a "treat-to-target" strategy congruent with specialty guidelines. METHODS: We have planned and initiated the Veterans Affairs (VA) Cooperative Study Program (CSP) 594, Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study. This large double-blind, non-inferiority trial will enroll 950 gout patients randomized to receive allopurinol or febuxostat. Patients will be followed for a total of 72 weeks encompassing 3 distinct 24-week study phases. During Phase I (0-24 weeks), participants will undergo gradual dose titration of ULT until achievement of serum uric acid (sUA) <6.0 mg/dL or <5.0 mg/dL if tophi are present. Dose escalation will not be allowed during final three study visits of Phase 2 (24-48 weeks) and during Phase 3 (48-72 weeks). The primary study outcome is the proportion of participants experiencing at least one gout flare during Phase 3. Subsequent to the 72-week study, participants will be followed passively for up to 10 years after the study to assess long-term health outcomes. CONCLUSION: With its completion, the VA Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study will demonstrate the central role of gradual ULT dose escalation and a treat-to-target strategy in gout management.

Fluids for prevention and management of acute kidney injury.

Fluids are the only known method of attenuating renal injury. Furthermore, whether for hydration, resuscitation or renal replacement therapy, fluid prescriptions must be tailored to the fluid and electrolyte, cardiovascular status and residual renal function of the patient. Different fluids have significantly different effects both on volume expansion as well as on the electrolyte and acid-base balance; while controversial, different fluids may even influence renal function differently. This systematic review focuses on fluids for prevention and management of acute kidney injury. We have reviewed the available evidence and have made recommendations for clinical practice and future studies.

Insertion of Temporary Dialysis Catheters with the Aid of Real-time Ultrasound.

Central venous catheters are widely used for both temporary and long-term angioaccess for hemodialysis. Insertion of these catheters is commonly performed using anatomic landmarks to guide vessel cannulation. Using traditional landmark-techniques, internal jugular venous catheter insertion is successful 82-88% of the time, with successful first-attempt cannulation of only 35-38%. Variations in anatomic relationships between the vein and surrounding structures may contribute to difficulty in venous cannulation using these traditional techniques. Real-time ultrasound guidance permits direct visualization of the target vein during catheter placement and is associated with increased successful cannulation (78-83% on first pass; 97-100% overall), a decreased number of attempts and a decreased complication rate. For this reason, we believe that real-time ultrasound-guided catheter insertion is superior to the traditional anatomic-landmark techniques and is emerging as the new standard of care.

Barriers to the delivery of adequate hemodialysis in ESRD Network 4.

Dialysis dose has been established as a determinant of morbidity and mortality in chronic hemodialysis patients. To identify remediable barriers to the delivery of adequate hemodialysis, we examined factors that affected adherence to prescribed dialysis dose. End-Stage Renal Disease (ESRD) Network 4 facilities that fell into the lowest quintile in measures of dialysis adequacy were studied. At the time of this study, Network 4 was composed of 178 dialysis facilities in Delaware and Pennsylvania. Those 29 facilities had an average delivered urea reduction ratio (URR) of <0.67 and/or 71% of patients with a URR of 0.65. (The mean URR value of Network 4 was 0. 699 with a compliance ratio of 80%.) Dialysis treatment sheets were reviewed for all patients in the 29 facilities for all treatments during a calendar week. Predialysis and postdialysis blood urea nitrogen (BUN) values from 1 treatment during this week were used to calculate URR and Kt/V. A total of 1,339 patients with a mean age of 61.9 +/- 15.1 years and a mean duration of ESRD of 3.4 +/- 3.3 years were dialyzed in the 29 units. Mean prescribed duration of dialysis (T) was 219 +/- 26 min. with a mean blood flow rate (BFR) of 393 +/- 62 mL/min. Concordance between the prescribed and delivered T (-5 min), BFR (-50 mL/min), and hemodialyzer were assessed, by patient, for each treatment (Tx). Characteristics of a delivered Kt/V < 1.2 were duration <4 hours, BFR < 350 mL/min, patient weight > 100 kg, and delivered BFR 50 mL/min less than prescribed BFR. Multivariate analysis of the relationship between delivered dose of dialysis and patients and treatment characteristics identified black race, male gender, and younger age as demographic factors associated with low delivered dose. Potential remediable barriers identified by this analysis included reduced treatment time (>10%) and use of catheters for angioaccess. These data suggest components of the dialysis process that might be targeted in future quality improvement projects to improve the adequacy of dialysis delivery.

Improving compliance with the dialysis prescription as a strategy to increase the delivered dose of hemodialysis: an ESRD Network 4 quality improvement project.

Delivery of an inadequate dose of hemodialysis is associated with a significant increase in the relative risk of both hospitalization and death. We hypothesized that noncompliance with the dialysis prescription, defined as failure to achieve the prescribed blood flow, failure to dialyze for the prescribed duration, or failure to use the prescribed dialyzer, was a significant factor in patients not achieving a urea reduction ratio (URR) of > or =0.65. We identified the 29 dialysis facilities in ESRD Network 4 that had the lowest average URR and/or lowest percent of patients with a URR > or =0.65 based on quarterly data reports. Each facility was surveyed by review of all dialysis treatment sheets from a single week by network staff to evaluate for noncompliance with the dialysis prescription. Facility-specific data were reported back to each facility. Each facility was required to develop a facility-specific quality improvement plan after receiving intensive education on the quality improvement process. After 9 months the facilities were resurveyed. Although the compliance with the dialysis prescription decreased from 54.0% to 53.6% (P =.026), the delivered URR increased from 0.679 +/- 0.072 to 0.688 +/- 0.070 (P =.026) with an increase in the percentage of patients with a URR > or = 0.65 from 69.7% to 75% (P =.0096). Kt/V increased from 1.37 +/- 0.26 to 1.41 +/- 0.27 (P =. 0001). Analysis of the process changes instituted by the individual facilities showed an increase in the prescribed dose of dialysis. Thus, although the process goal of improved compliance with the dialysis prescription was not achieved, the outcome goal of an increased delivered dose of dialysis was met through an alternative process change of an augmented dialysis prescription.

Determinants of ceftriaxone clearance by continuous venovenous hemofiltration and hemodialysis.

STUDY OBJECTIVE: To guide individual ceftriaxone dosages in patients receiving continuous renal replacement therapy. DESIGN: Prospective, outpatient study. SETTING: University-affiliated general clinical research center. PATIENTS: Eight patients receiving hemodialysis. INTERVENTION: We performed controlled clearance studies with three hemofilters: an acrylonitrile copolymer 0.6 m2 (AN69), polymethylmethacrylate 2.1 m2 (PMMA), and polysulfone 0.65 m2 (PS). MEASUREMENTS AND MAIN RESULTS: Subjects received ceftriaxone 1000 mg intravenously before the start of a clearance study. The concentration of ceftriaxone in multiple plasma and dialysate-ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (Cl(diffusion)) and sieving coefficients (SC) of ceftriaxone, urea, and creatinine were compared by a mixed-model repeated-measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and patient as a random effect. The fraction of ceftriaxone bound to plasma proteins was 43 +/- 15% (range 13-92%). Concentration dependence was evident in all three groups. The fraction unbound to plasma proteins (f(up)) at the time that SCs were determined was significantly lower in the PS group (0.16 +/- 0.07) than the AN69 group (0.30 +/- 0.17, p<0.01), but similar to that in the PMMA group (0.27 +/- 0.12). Despite the higher f(up), the SC of unbound ceftriaxone with the AN69 filter (0.48 +/- 0.13) was significantly lower than values for the PMMA (0.86 +/- 0.33) and PS (0.82 +/- 0.22) groups (p<0.05). Continuous venovenous hemofiltration clearance of urea and unbound ceftriaxone increased significantly only for the PMMA (p=0.006) and PS (p=0.015) filters when the ultrafiltration rate was increased. Significant linear relationships (p<0.0001) were observed between Cl(diffusion) of unbound ceftriaxone and clearance of urea for all three filters: AN69 slope = 0.57, PMMA slope = 0.90, and PS slope = 1.02. The slope of this relationship for the AN69 filter was significantly lower than for the other two filters. CONCLUSION: Ceftriaxone clearance was significantly increased and membrane dependent during continuous venovenous hemofiltration and continuous venovenous hemodialysis. Thus individual ceftriaxone dosages for patients receiving continuous renal replacement therapies should incorporate extracorporeal clearance.

Determinants of ceftazidime clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis.

Although several dosage adjustment regimens have been proposed, there is little quantitative information to guide the initiation of ceftazidime therapy in patients who are receiving continuous renal replacement therapy. To determine the clearance of ceftazidime by continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), we performed controlled clearance studies with stable hemodialysis patients with three hemofilters: a 0.6-m(2) acrylonitrile copolymer (AN69; Hospal) filter, a 2.1-m(2) polymethylmethacrylate filter (PMMA; Toray) filter and a 0.65-m(2) polysulfone (PS; Fresenius) filter. Subjects received 1,000 mg of ceftazidime intravenously prior to the start of a clearance study. The concentration of ceftazidime in multiple plasma and dialysate or ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (CI(diffusion)) and sieving coefficients of ceftazidime were compared by a mixed-model repeated-measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and the patient as a random effect. The fraction of ceftazidime bound to plasma proteins was 17%+/-7% (range, 10 to 25%). The clearances of ceftazidime, urea, and creatinine by CVVHD were essentially constant at blood flow rates of 75 to 250 ml/min for all three filters. Significant linear relationships (P<0.0001) were observed between CI(diffusion) of ceftazidime and clearance of urea for all three filters: AN69 (slope = 0.83), PMMA (slope = 0.89), and PS (slope = 1.03). Ceftazidime clearance was membrane independent during CVVH and CVVHD. CVVH and CVVHD can significantly augment the clearance of ceftazidime. Dosing strategies for initiation of ceftazidime therapy in patients receiving CVVH and CVVHD are proposed.

Factors affecting system clotting in continuous renal replacement therapy: results of a randomized, controlled trial.

BACKGROUND: System clotting and the anticoagulation techniques employed to prevent it are important causes of morbidity in continuous renal replacement therapy (CRRT). Different means have been employed in attempts to prolong system lifespan while minimizing complications. SUBJECTS, MATERIALS AND METHODS: To determine whether augmenting blood flow and flush frequency could reduce clotting frequency, we compared system lifespan in a standard blood flow and saline flush group (125 ml/min and 100 ml once hourly, respectively) to an augmented blood flow and saline flush group (200-250 ml/min and 100 ml twice hourly). A total of 34 patients treated with continuous venovenous hemodialysis were randomized to receive either the standard or augmented regimens in a prospective trial conducted between August 1995 and March 1997. A total of 130 systems were studied. RESULTS: Based on intention-to-treat analysis, there was no difference in time to clot between the two groups. In a multivariate analysis of the outcome, red blood cell and platelet transfusion during CRRT were significantly associated with decreased clotting, and systemic heparin infusion significantly prolonged lifespan of CRRT systems. CONCLUSION: Increasing blood flow and flush frequency does not prevent clotting in CRRT. Since this intervention is more costly than standard treatment, its use cannot be justified.

Treatment of edematous disorders with diuretics.

Generalized edema results from alterations in renal sodium homeostasis that ultimately result in an expansion of extracellular fluid volume and accumulation of interstitial fluid. The common edematous disorders include congestive heart failure, cirrhosis, nephrotic syndrome, and renal insufficiency. The abnormalities of sodium homeostasis contributing to edema formation in each condition are discussed. Management of volume homeostasis, with an emphasis on the role of diuretic therapy, is reviewed.

Duodenal obstruction in polycystic kidney disease. Case report and review of the literature.

Polycystic kidney disease in a common inherited disorder accounting for 8-10% of cases of end-stage renal disease. The enlarged kidneys often produce pain and hematuria but rarely obstruction of surrounding organs. We report a case of autosomal dominant polycystic kidney disease producing symptomatic duodenal obstruction and malnutrition. Duodenal obstruction should be considered in the differential diagnosis of a patient with polycystic kidney disease and intermittent or persistent nausea and vomiting.

Determinants of vancomycin clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis.

The clearance of vancomycin is significantly reduced in patients with acute, as well as, chronic renal failure. Although multiple-dosage regimen adjustment techniques have been proposed for these patients, there is little quantitative data to guide the individualization of vancomycin therapy in acute renal failure patients who are receiving continuous renal replacement therapy (CRRT). To determine appropriate vancomycin dosing strategies for patients receiving continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), we performed controlled clearance studies in five stable hemodialysis patients with three hemofilters: an acrylonitrile copolymer 0.6 m2 (AN69), polymethylmethacrylate 2.1 m2 (PMMA), and polysulfone 0.65 m2 (PS). Patients received 500 mg of vancomycin intravenously at least 12 hours before the start of the clearance study. The concentration of vancomycin in multiple plasma and dialysate/ultrafiltrate samples was determined by EMIT (Syva, Palo Alto, CA). The diffusional clearance and sieving coefficient (SC) of vancomycin were compared by a mixed-model repeated-measures analysis of variance (ANOVA) with filter and blood (Q(B)), dialysate inflow (Q(DI)), or ultrafiltration rate (Q(UF)) as the main effects and patient as a random effect. Vancomycin was moderately protein bound in these patients; free fraction ranged from 49% to 83%. The SCs of the three filters were similar and significantly correlated with the free fraction of vancomycin (P = 0.01; r2 = 0.465). Significant linear relationships were observed between the diffusional clearance of vancomycin and Q(DI) for all three filters: AN69 (slope = 0.482; r2 = 0.880); PMMA (slope = 0.853; r2 = 0.966); and PS (slope = 0.658; r2 = 0.887). The slope of this relationship for the PMMA filter was significantly greater than that of the AN69 and PS filters. The clearance of vancomycin, urea, and creatinine, however, was essentially constant at all Q(B)s for all three filters. Thus, the clearance of vancomycin was not membrane dependent during CVVH. However, during CVVHD, membrane dependence of vancomycin clearance was noted at a Q(DI) greater than 16.7 mL/min; vancomycin clearance with PMMA at a Q(DI) of 25 mL/min was 66% and 43% greater than that with the AN69 and PS filters, respectively. CVVH (62% to 262%) and CVVHD (90% to 540%) can significantly augment the clearance of vancomycin in acute renal failure patients. Dosing strategies for individualization of vancomycin therapy in patients receiving CVVH and CVVHD are proposed.

Hyperkalemia in hospitalized patients: causes, adequacy of treatment, and results of an attempt to improve physician compliance with published therapy guidelines.

BACKGROUND: Hyperkalemia is a common, potentially life-threatening disorder. Electrocardiograms are considered to be sensitive indicators of the presence of hyperkalemia. Since the treatment of hyperkalemia involves relatively few maneuvers and because its success can be objectively scored, we investigated how physicians manage this disorder and how successful their prescribed therapy is. We also sought to determine whether treatment could be improved by providing the treating physicians with therapy guidelines on a real-time basis. METHODS: Consecutive patients with hyperkalemia were identified by review of laboratory records. During the observation-only phase of the study, demographic data, contributing causes, electrocardiogram findings, treatments used, compliance with prescribing guidelines, and patient outcome were recorded. During the subsequent notification phase of the study, treatment recommendations were sent to the patient's ward when the elevated potassium value was noted. The same outcome data were collected. RESULTS: There were 127 episodes of hyperkalemia during the observation-only phase and 115 during the notification phase. No patients died or had life-threatening cardiac arrhythmias. Electrocardiographic abnormalities consistent with hyperkalemia were observed in only 14% of episodes. Renal failure (77%), drugs (63%), and hyperglycemia (49%) contributed to most episodes. Treatments used were exchange resin (51%), insulin (46%), calcium (36%), bicarbonate (34%), and albuterol (4%). The agents were equally efficacious. The time to first treatment was shorter in patients with potassium levels of 6.5 mmol/L or more than in patients with lower values (2.1 +/- 2.2 vs 2.8 +/- 2.4 hours; P<.05). Treatment was better in the intensive care unit than on regular wards. Only 39% of episodes during the observation-only period met the predetermined criteria for monitoring and diagnosis, initial treatment, and follow-up. During the notification period, physician performance was no better; only 42% of episodes met all criteria. The laboratory transmitted a copy of the guidelines to the patient's ward only 38% of the time. In a separate analysis of these episodes, there was no improvement in treatment. Physicians who did not receive the notification fulfilled all treatment criteria more often than physicians who did (50% vs 30%; P<.05). CONCLUSIONS: Although treatment of hyperkalemia was frequently suboptimal, no serious arrhythmias and no deaths complicated management of 242 episodes of severe hyperkalemia. A narrowly targeted effort to improve physician management of a disorder with discrete treatment options did not improve therapy.

Hypernatremia.

Renal water conservation minimizes the progression of hypernatremia, but the ultimate defense against progressive hypernatremia is the stimulation of thirst by hypertonicity with a resultant increase in water ingestion. Defects in thirst may result from focal lesions involving the hypothalamic osmoreceptors, but more commonly are the result of lesions that impair higher cortical processes required for thirst perception and water ingestion. In response to hypernatremia, the brain undergoes adaptive responses to minimize osmotic shrinkage. Initially there is a rapid uptake of electrolytes, while a slower adaptive phase involves the accumulation of organic osmolytes. The rate at which these solutes can be extruded from the brain dictates the rate at which water replacement can be safely administered during treatment. The incidence of hypernatremia ranges from less than 1% to more than 3% in clinical series. While hypernatremia in nonhospitalized patients is predominantly a disease of the elderly, and is commonly a manifestation of infection or inadequate nursing care, hospital-acquired hypernatremia occurs in a patient population more closely resembling the general hospitalized population and results from inadequate water prescription to patients who are unable to self-regulate water intake. Mortality rates range from approximately 40% to more than than 60%.

Diffusive vs. convective therapy: effects on mediators of inflammation in patient with severe systemic inflammatory response syndrome.

OBJECTIVE: To compare two forms of continuous renal replacement therapy, continuous venovenous hemofiltration (CVVH) vs. continuous venovenous hemodialysis (CVVHD), in terms of the removal of inflammatory mediators from the blood of patients with systemic inflammatory response syndrome and acute renal failure. DESIGN: Randomized crossover, clinical study. SETTING: University teaching hospital. PATIENTS: Thirteen patients with systemic inflammatory response syndrome and acute renal failure receiving continuous renal replacement therapy. INTERVENTION: Patients were randomized to receive either convective clearance using CVVH or diffusive clearance using CVVHD for the first 24 hrs, followed by the other modality for 24 hrs. All treatments utilized AN69 hemofilters. CVVH was performed with an ultrafiltration rate of 2 L/hr and CVVHD with a dialysis outflow rate of 2 L/hr. MEASUREMENTS AND MAIN RESULTS: Plasma and ultrafiltrate concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10, and sL-selectin were measured at 0, 1, 3, 6, 12, and 24 hrs by radioimmunoassay. Plasma endotoxin concentrations were also measured at 0, 12, and 24 hrs by chromogenic assay. CVVH was associated with a 13% decrease in plasma TNF-alpha concentrations compared with a 23% increase while on CVVHD (p < .05). Mean plasma concentrations of IL-6, IL-10, and sL-selectin were unchanged over time and between therapies. Only minimal amounts of mediators were recovered in the effluents with either therapy except for IL-6. The clearances for IL-6 were different between therapies, 1.9+/-0.8 (SD) mL/min for CVVHD and 3.3+/-1.5 mL/min for CVVH, (p< .01). Plasma endotoxin concentrations were not different between therapies. CONCLUSION: CVVH resulted in a decrease in plasma TNF-alpha concentrations as compared with CVVHD, while the type of transport mechanism used did not influence plasma concentrations of IL-6, IL-10, soluble L-selectin, or endotoxin. Differences in clearance for IL-6 between CVVH and CVVHD did not translate into significant changes in circulating IL-6 concentrations.

Hyponatremia and hypernatremia.

Hyponatremia and hypernatremia are common electrolyte disorders resulting from disorders in water homeostasis. Hyponatremia usually results from defects in free water excretion, although increased intake may also contribute. The treatment of hyponatremia has been controversial because of the high associated morbidity and mortality and the observation that rapid correction of hyponatremia is associated with the development of central pontine myelinolysis. Mild hyponatremia should be treated with water restriction alone, whereas severe acute or symptomatic hyponatremia should initially be corrected rapidly until symptoms resolve followed by more gradual correction. In all cases, treatment should be individualized on the basis of severity, cause, and duration of the hyponatremia. Hypernatremia results from impaired water ingestion, although increased water losses are often contributory. Hospital-acquired hypernatremia is usually iatrogenic because of inadequate water prescription and is therefore preventable. Hypernatremia is also associated with high morbidity and mortality, both as a result of the underlying disease and inadequate treatment. The primary treatment of hypernatremia is water replacement-repleting water deficits and replacing ongoing losses. Additional treatment should be directed at eliminating excess water losses.

FK-506 and rapamycin but not cyclosporin inhibit aldosterone-stimulated sodium transport in A6 cells.

The immunosuppressants cyclosporin A (CyA), FK-506, and rapamycin (RAP) have multiple actions on target cells that appear to be mediated by interaction of drug-binding protein complexes. Both FK-506 and CyA, but not RAP, inhibit the Ca2(+)-dependent phosphatase, calcineurin, and in so doing have been found to inhibit Na(+)-K(+)-ATPase activity in various nephron segments. Of interest, FK-506 and RAP, but not CyA, are bound by the steroid receptor-associated FK-506-binding heat shock protein of 56 kDa, HSP56. To determine the physiological effect of this interaction on a steroid-mediated phenomenon, the effect of these agents on steroid-mediated Na+ transport in A6 cells was investigated. Aldosterone stimulation of Na+ transport and Na(+)-K(+)-ATPase activity are significantly inhibited by prolonged incubation with FK-506 and RAP. Although CyA inhibits basal Na(+)-K(+)-ATPase activity, it has no effect on aldosterone-induced Na+ transport or the aldosterone-induced increase in Na(+)-K(+)-ATPase activity. FK-506 inhibits the aldosterone-induced synthesis of G alpha i-3 protein but has no effect on glucocorticoid receptor number as quantified by Western blotting. The results suggest that FK-506 and RAP inhibit steroid-mediated Na+ transport at some pretranslational site. The common interaction of these agents with the steroid receptor-associated HSP56 might account for these findings.

Regulation of a sodium channel-associated G-protein by aldosterone.

The action of aldosterone to increase apical membrane permeability in responsive epithelia is thought to be due to activation of sodium channels. This channel is regulated, in part, by G-proteins, but it is not known if this mechanism is regulated by aldosterone. We report that aldosterone stimulates the expression of the 41-kDa alphai3 subunit of the heterotrimeric GTP-binding proteins in A-6 cells. Both mRNA and the total amount of this protein are increased by aldosterone. The G-protein is palmitoylated in response to the steroid, and the newly synthesized subunit is found to co-localize with the sodium channel. Aldosterone stimulation of sodium transport is significantly inhibited by inhibition of palmitoylation. These results suggest that aldosterone regulates sodium channel activity in epithelia through stimulation of the expression and post-translational targeting of a channel regulatory G-protein subunit.

Hypernatremia in hospitalized patients.

OBJECTIVE: To determine the incidence, clinical characteristics, and outcome for general medical-surgical hospital patients with hypernatremia. DESIGN: A prospective cohort study. SETTING: A 942-bed urban university hospital. PATIENTS: All patients who developed a serum sodium concentration of 150 mmol/L or greater during a 3-month observation period. MEASUREMENTS: Daily fluid balance, mental status, and serum and urine electrolytes and osmolality. RESULTS: 103 patients were identified. Eighteen patients were hypernatremic on hospital admission, and 85 developed hypernatremia during hospitalization. Patients who developed hypernatremia during hospitalization were younger than patients who developed hypernatremia before hospital admission (mean age +/- SD, 58.9 +/- 19.2 years compared with 76.6 +/- 16.6 years; P < 0.01) but did not differ in age from the patients of the general hospitalized population. Eighty-nine percent of patients who developed hypernatremia during hospitalization had urine concentrating defects, primarily as the result of the use of diuretics or of solute diuresis, whereas only 50% of patients who were hypernatremic on admission could be shown to have concentrating defects (P < 0.01). Fifty-five percent of all hypernatremic patients had increased insensible water losses, and 35% had increased enteral water losses. Eighty-six percent of patients with hospital-acquired hypernatremia lacked free access to water, 74% had enteral water intake of less than 1 L/d, and 94% received less than 1 L of intravenous electrolyte-free water per day during the development of hypernatremia. No supplemental electrolyte-free water was prescribed during the first 24 hours of hypernatremia in 49% of patients. The duration of hypernatremia was shorter in patients who were hypernatremic on admission (median duration, 3 days) than in patients with hospital-acquired hypernatremia (median duration, 5 days; P < 0.05). Mortality was 41% for all patients, but hypernatremia was judged to have contributed to mortality in only 16% of patients. CONCLUSIONS: Although the development of hypernatremia before hospital admission occurs primarily in geriatric patients, hospital-acquired hypernatremia was more common in our cohort and had an age distribution similar to that of the general hospitalized population. Hospital-acquired hypernatremia was primarily iatrogenic, resulting from inadequate and inappropriate prescription of fluids to patients with predictably increased water losses and impaired thirst or restricted free water intake or both. Treatment of hypernatremia is often inadequate or delayed. Efforts to manage hypernatremia better and altogether avoid hospital-acquired hypernatremia should focus on both physician education and the development of hospital systems to prevent errors in fluid prescription.

Failure of low molecular weight dextran to prevent clotting during continuous renal replacement therapy.

Clotting of the extracorporeal circuit during continuous renal replacement therapy results in decreased ultrafiltration rates, impaired solute clearance and, ultimately, occlusion of the extracorporeal circuit. The authors conducted an open-label randomized controlled trial to determine whether low molecular weight dextran could prevent hemofilter clotting in patients undergoing continuous venovenous hemodialysis. Eleven patients were randomized to receive a continuous infusion of 10% low molecular weight dextran at 25 mL/hr; 8 patients served as control subjects. No differences in the frequency of hemofilter clotting or hemofilter lifespan were detected. The authors concluded that continuous infusion of low dose low molecular weight dextran is not effective in preventing clotting during continuous renal replacement therapy.