Anemia treatment with Q2W darbepoetin alfa in patients with chronic kidney disease naïve to erythropoiesis-stimulating agents.

OBJECTIVE: To evaluate the efficacy and safety of darbepoetin alfa dosed every-other-week (Q2W) to treat anemia in subjects with chronic kidney disease (CKD), not receiving dialysis, who were naïve to erythropoiesis-stimulating agent (ESA) therapy. RESEARCH DESIGN AND METHODS: This was an open-label, multicenter, single-arm study enrolling ESA-naïve CKD subjects with baseline hemoglobin (Hb) < 11.0 g/dL. Q2W darbepoetin alfa treatment was initiated at a dose of 0.75 microg/kg and titrated to achieve and maintain Hb levels at 11.0-13.0 g/dL. Treatment was administered from week 1 to week 19. MAIN OUTCOME MEASURES: The primary endpoint was the proportion of subjects who achieved Hb > or = 11 g/dL at any study visit, except in week 1. Hb levels, darbepoetin alfa dose, and safety were also assessed. RESULTS: Of the 128 subjects who received at least one dose of darbepoetin alfa and of the subjects who completed the study, 118 (92%) and 112 (97%), respectively, achieved a Hb > or = 11 g/dL in a median time of 5 weeks. Median darbepoetin alfa dose at week 1 and at the time of achieving a Hb > or = 11 g/dL were 60 and 80 microg, respectively. Darbepoetin alfa was well-tolerated, and short-term adverse events were consistent with those expected in CKD subjects. CONCLUSIONS: This study demonstrates that de novo Q2W darbepoetin alfa was effective in correcting and maintaining Hb levels in ESA-naïve subjects with CKD who were not receiving dialysis. Study limitations, including lack of a control arm for the study and multiple race information for subjects, must be considered in interpreting the results. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00112008.

An open-label study of darbepoetin alfa administered once monthly for the maintenance of haemoglobin concentrations in patients with chronic kidney disease not receiving dialysis.

OBJECTIVE: To demonstrate the efficacy and safety of once-monthly (QM) darbepoetin alfa administration in maintaining haemoglobin (Hb) 11.0-13.0 g dL(-1) in subjects with chronic kidney disease (CKD) not receiving dialysis and previously treated with darbepoetin alfa every other week (Q2W). SUBJECTS: This open-label study enrolled subjects > or =18 years of age who had glomerular filtration rate > or =15 and < or =60 mL min(-1)/1.73 m(2), had Hb 11.0-13.0 g dL(-1), and were receiving Q2W darbepoetin alfa. DESIGN: Subjects were switched to QM darbepoetin alfa therapy for 28 weeks; the QM dose was titrated to maintain Hb levels. Primary end-point: proportion of subjects maintaining Hb > or =11.0 g dL(-1) during the final 8 weeks of the study (evaluation phase). Secondary end-points: Hb concentration during evaluation, darbepoetin alfa dose during the study, adverse events, laboratory parameters, and blood pressure. RESULTS: The study enrolled 152 subjects (female 52%, white 64%). Mean Hb > or =11.0 g dL(-1) during evaluation was achieved by 76% of the 150 subjects who received at least one dose of darbepoetin alfa [95% confidence interval (CI): 68%, 83%]. Mean (SD) Hb during evaluation was 11.71 (0.92) g dL(-1). Eighty-five per cent of 129 subjects who completed the study (95% CI: 78%, 91%) had Hb > or =11.0 g dL(-1) during evaluation. The dose of darbepoetin alfa over the study period was median (95% CI) 124.4 mug (106.2, 140.0). Darbepoetin alpha administered QM was well tolerated in study subjects. CONCLUSION: Darbepoetin alpha administered QM maintained Hb in study subjects with CKD not receiving dialysis.

Functional characterization and kinetic studies of an ancestral lamprey GnRH-III selective type II GnRH receptor from the sea lamprey, Petromyzon marinus.

The recently cloned lamprey GnRH receptor was shown to have several unique features, including the longest intracellular C-terminal tail (120 amino acids (aa)) of any previously described GnRH receptor. In the current study, a series of experiments were performed examining cAMP responses, binding kinetics, whole cell competitive binding assays and internalization studies of the lamprey GnRH receptor using a series of three C-terminal tail truncations (80 aa, 40 aa and 0 aa) to better describe the functional significance of this unique vertebrate GnRH receptor. Activation of the lamprey GnRH receptor was shown to stimulate cAMP production in a dose-dependent manner when treated with either lamprey GnRH-I (LogEC50 -6.57+/-0.15) or lamprey GnRH-III (LogEC(50) -8.29+/-0.09). Truncation analysis indicated that the membrane proximal 40 aa of the lamprey GnRH receptor C-terminal tail contain a motif required for cAMP accumulation. Saturation binding assays using the wild type and truncated lamprey GnRH receptors revealed that all of three truncated lamprey GnRH receptors were capable of binding lamprey GnRH-I. Competitive, intact cell-binding assays suggested that the lamprey GnRH receptor is lamprey GnRH-III selective, based on the observed pharmacological profile: lamprey GnRH-III (Inhibitory constant (Ki) 0.708+/-0.245 nM)=chicken GnRH-II (Ki 0.765+/-0.160 nM) > mammalian GnRH (Ki 12.9+/-1.96 nM) > dAla(6)Pro(9)NEt mammalian GnRH (Ki 21.6+/-9.68 nM) > lamprey GnRH-I (Ki 118.0+/-23.6). Finally, the lamprey GnRH receptor was shown to undergo rapid ligand-dependent internalization, which was significantly diminished in the tail-less truncated form. We have shown from our current and our previous structural studies that this unique lamprey GnRH receptor shares several characteristics of both type I and type II GnRH receptors which suggests that this receptor has retained ancestral characteristics that can provide insight into the function and evolution of the vertebrate GnRH receptor family.

Pulmonary alveolar proteinosis causing severe hypoxemic respiratory failure treated with sequential whole-lung lavage utilizing venovenous extracorporeal membrane oxygenation: a case report and review.

Pulmonary alveolar proteinosis is characterized by the accumulation of proteinaceous material in the alveoli leading to varying degrees of impairment in gas exchange. Generally, the degree of hypoxemia is mild, and it is rare to have respiratory failure requiring mechanical ventilation. We present a 53-year-old woman with the most severe degree of hypoxemia associated with alveolar proteinosis reported in the English-language adult literature. Her therapy of sequential whole-lung lavage performed while receiving venovenous extracorporeal membrane oxygenation in one operative session is the first reported successful use of this approach.

Managing the lifeline: preemptive access management for better outcomes for hemodialysis patients and programs. Medical Review Board of The Renal Network, Inc.

Problems with vascular access for hemodialysis patients contribute substantially to the morbidity, mortality, and high costs associated with renal replacement therapy. Data from the Network 9/10 Regional Hemodialysis Vascular Access Quality Improvement Project show evidence of incremental improvements, with more native vein fistulae and fewer grafts. However, increased numbers of catheters were observed, and still fully 32% of the catheters in place were associated with no internal access created after more than 90 days on dialysis. This article reviews recent contributions to understanding patterns of access-related care, pathophysiology of vascular access complications, and new approaches to achieving the preferred native vein arteriovenous fistulae. A financial analysis shows that dialysis units that employ dedicated access management personnel can expect bottom-line benefits that will easily cover the added expense. These benefits will be in addition to improvements in morbidity and mortality for patients.

The impact of long-term acute-care facilities on the outcome and cost of care for patients undergoing prolonged mechanical ventilation.

OBJECTIVES: To compare the 6-month mortality rate of chronically ventilated patients treated either exclusively in a traditional acute-care hospital or transferred during hospitalization to a long-term acute-care facility. To analyze the hospital cost of care and estimate the amount of uncompensated care incurred by acute-care hospitals under the Medicare prospective payment diagnostic related groups system. DESIGN: Retrospective chart review and questionnaire. SETTING: Fifty-four acute-care referral hospitals and 26 longterm acute-care institutions. PATIENTS: A total of 432 ventilated patients selected from 3,266 patients referred but not transferred to a study long-term acute-care facility and 1,702 ventilated patients from 4,174 patients referred and then subsequently transferred to the long-term acute-care facility. Six-month outcomes were determined for the subgroup of patients > or =65 yrs old (279 and 1,340 patients, respectively). Hospital charges were available for 192 of the 279 nontransferred patients who were > or =65 yrs old and 1,332 of the 1,340 transferred patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The 6-month mortality rate was 67.4% for the 279 nontransferred patients and 67.2% for the 1,340 transferred patients. On multiple regression analysis, variables associated with the 6-month mortality rate included initial admitting diagnosis, age, the acute physiology score, and presence of decubitus ulcer. After controlling for these variables, there was no significant difference in 6-month mortality rate, but admission to the long-term acute-care facility was associated with a longer mean survival time. Average total hospital costs for the 192 nontransferred patients was $78,474, and estimated Medicare reimbursement was $62,472, resulting in an average of $16,002 of uncompensated care per patient. Estimated costs for the long-term acute-care facility admissions were $56,825. CONCLUSIONS: Patients undergoing prolonged ventilation have high hospital and 6-month mortality rates, and 6-month outcomes are not significantly different for those transferred to long-term acute-care facilities. These patients generate high costs, and acute-care hospitals are significantly underreimbursed by Medicare for these costs. Acute-care hospitals can reduce the amount of uncompensated care by earlier transfer of appropriate patients to a long-term acute-care facility.

Use of standardized ratios to examine variability in hemodialysis vascular access across facilities. Medical Review Board of The Renal Network, Inc.

The type of hemodialysis vascular access (catheter, fistula, graft) is an important determinant of patient morbidity and dialysis efficiency. The relative importance of patient versus provider factors in determining type of vascular access is unclear. We sought to develop a quality improvement tool that adjusts for differences in patient characteristics, thereby allowing examination of provider-related variability in types of vascular access used across facilities. We examined 15,339 patients from 216 chronic hemodialysis units in Indiana, Kentucky, Ohio, and Illinois and found that 20% of patients had catheters, 24% had fistulas, and 56% had grafts. Young, male, and white patients were more likely to have fistulas, whereas old, female, and black patients were more likely to have grafts. Diabetics were more likely to have catheters and less likely to have fistulas. New patients were more likely to have catheters and less likely to have grafts. A facility specific standardized catheter ratio (SCR), standardized fistula ratio (SFR), and standardized graft ratio (SGR) were calculated based on the actual number of patients with each type of vascular access divided by the expected number adjusted for patient characteristics. Facility SCRs ranged from 0.00 to 2.87. Of the 216 facilities, 38 (18%) had an SCR significantly less than 1.00, and 32 (15%) had an SCR significantly greater than 1.00. Similar variability was observed in SFRs and SGRs. In conclusion, the type of vascular access varies greatly across facilities. Use of standardized access ratios adjusted for patient characteristics may help providers examine processes of care that contribute to variability in access use. Analogous to the standardized mortality ratio, the SCR, SFR, and SGR should be effective quality improvement tools.

Barriers to adequate delivery of hemodialysis.

Mortality rates among American hemodialysis patients are the highest in the industrialized world. Measures of delivered dialysis (Kt/V) correspond strongly with survival and are estimated to be inadequate in one third of patients. We sought to determine the importance of potential barriers to adequate dialysis, including patient-related and technical factors. Using a cross-sectional study design, we abstracted the charts of 721 randomly selected patients from all 22 chronic hemodialysis units in northeast Ohio. For each of 1,836 treatments provided to these patients, we assessed delivered dialysis (Kt/V) and patient-related factors (ie, hypotension, intradialytic symptoms, and treatment time missed due to noncompliance or transportation problems) and technical factors (ie, dialysis prescription, type of vascular access, clotting, and dialyzer reuse). We used hierarchical regression analysis to determine which potential barriers were independently related to delivered dialysis after adjustment for patient demographic and medical characteristics. Barriers independently related to dialysis delivery (all P values < 0.001) included patient noncompliance, present in 3% of treatments; low dialysis prescription, 14%; use of a catheter for vascular access, 11%; and clotting, 1%. The prevalence of identified barriers varied dramatically across facilities (eg, the prevalence of low dialysis prescription ranged from 0% to 37%, while the prevalence of catheter use ranged from 3% to 28%). In conclusion, patient noncompliance, low dialysis prescription, catheter use, and clotting are the most important barriers to dialysis delivery. Further work is needed to develop interventions to overcome these barriers and to determine the effect of such interventions on dialysis adequacy and patient survival.

Ion channels in human THP-1 monocytes.

The THP-1 human monocytic leukemia cell line is a useful model of macrophage differentiation. Patch clamp methods were used to identify five types of ion channels in undifferentiated THP-1 monocytes. (i) Delayed rectifier K+ current, IDR, was activated by depolarization to potentials positive to -50 mV, inactivated with a time constant of several hundred msec, and recovered from inactivation with a time constant approximately21 sec. IDR was inhibited by 4-aminopyridine (4-AP), tetraethylammonium (TEA+), and potently by charybdotoxin (ChTX). (ii) Ca-activated K+ current (ISK) dominated whole-cell currents in cells studied with 3-10 micron [Ca2+]i. ISK was at most weakly voltage-dependent, with reduced conductance at large positive potentials, and was inhibited by ChTX and weakly by TEA+, Cs+, and Ba2+, but not 4-AP or apamin. Block by Cs+ and Ba2+ was enhanced by hyperpolarization. (iii) Nonselective cation current, Icat, appeared at voltages above +20 mV. Little time-dependence was observed, and a panel of channel blockers was without effect. (iv) Chloride current, ICl, was present early in experiments, but disappeared with time. (v) Voltage-activated H+ selective current is described in detail in a companion paper (DeCoursey & Cherny, 1996. J. Membrane Biol. 152:2). The ion channels in THP-1 cells are compared with channels described in other macrophage-related cells. Profound changes in ion channel expression that occur during differentiation of THP-1 cells are described in a companion paper (DeCoursey et al., 1996. J. Membrane Biol. 152:2).

Ion channel expression in PMA-differentiated human THP-1 macrophages.

Ion channel expression was studied in THP-1 human monocytic leukemia cells induced to differentiate into macrophage-like cells by exposure to the phorbol ester, phorbol 12-myristate 13-acetate (PMA). Inactivating delayed rectifier K+ currents, IDR, present in almost all undifferentiated THP-1 monocytes, were absent from PMA-differentiated macrophages. Two K+ channels were observed in THP-1 cells only after differentiation into macrophages, an inwardly rectifying K+ channel (IIR) and a Ca2+-activated maxi-K channel (IBK). IIR was a classical inward rectifier, conducting large inward currents negative to EK and very small outward currents. IIR was blocked in a voltage-dependent manner by Cs+, Na+, and Ba2+, block increasing with hyperpolarization. Block by Na+ and Ba2+ was time-dependent, whereas Cs+ block was too fast to resolve. Rb+ was sparingly permeant. In cell-attached patches with high [K+] in the pipette, the single IIR channel conductance was approximately 30 pS and no outward current could be detected. IBK channels were observed in cell-attached or inside-out patches and in whole-cell configuration. In cell-attached patches the conductance was approximately 200-250 pS and at potentials positive to approximately 100 mV a negative slope conductance of the unitary current was observed, suggesting block by intracellular Na+. IBK was activated at large positive potentials in cell-attached patches; in inside-out patches the voltage-activation relationship was shifted to more negative potentials by increased [Ca2+]. Macroscopic IBK was blocked by external TEA+ with half block at 0.35 mM. THP-1 cells were found to contain mRNA for Kv1.3 and IRK1. Levels of mRNA coding for these K+ channels were studied by competitive PCR (polymerase chain reaction), and were found to change upon differentiation in the same direction as did channel expression: IRK1 mRNA increased at least 5-fold, and Kv1.3 mRNA decreased on average 7-fold. Possible functional correlates of the changes in ion channel expression during differentiation of THP-1 cells are discussed.

Medical effectiveness of esophageal balloon pressure manometry in weaning patients from mechanical ventilation.

OBJECTIVE: To determine the efficacy of a new respiratory monitor, which uses esophageal balloons, in aiding clinicians attempting to wean patients from mechanical ventilation. DESIGN: Prospective study of patients who were deemed ready to be weaned after having required mechanical ventilation for a minimum of 3 days. Each of the patients served as his or her own control. SETTING: University medical intensive care unit. PATIENTS: The series consisted of 23 consecutive patients who were ready to wean from mechanical ventilation. INTERVENTIONS: Before the onset of the study, two weaning strategies were developed. One strategy involved using clinically available weaning parameters. The other strategy involved using esophageal balloon data that was recorded via a new respiratory monitor. Each of the weaning strategies resulted in the development of a scoring system that could be rigidly adhered to and which determined, without bias, to what extent the patient could be weaned each day. Rigid criteria were also developed to determine whether the weaning trial was successful or not. The two strategies were then compared to determine the ability of the strategy to shorten ventilatory time. MEASUREMENTS AND MAIN RESULTS: Each patient was evaluated daily by the two weaning protocols. At each weaning step, the two protocols were compared with respect to degree of aggressiveness and tolerance of the weaning maneuver by the patient. A protocol was judged superior if it resulted in more aggressive weaning without increased patient intolerance. The clinicians evaluating the patient with the clinical protocol could accelerate or retard the number of weaning steps by one step, based on the patient's clinical state and the clinician's experience. There was no such freedom in the esophageal protocol. The major finding was that in 40.5% of the instances, the protocol involving the esophageal balloon resulted in more aggressive weaning without patient intolerance. In 11.6% of the cases, the clinical protocol was more aggressive. Both protocols predicted the same number of weaning steps 39.8% of the time. In all these instances, the patient tolerated the weaning suggested. The use of data from the esophageal protocol resulted in weaning the patients 1.68 days faster than the use of data from the clinical protocol. CONCLUSIONS: The respiratory monitor, using esophageal balloon technology, is effective in that it can provide the clinician with data that can result in more aggressive weaning from mechanical ventilation without an increase in patient intolerance. The duration of mechanical ventilation can be shortened when these data are applied via a rigidly controlled weaning strategy.

Bronchoscopic procedures in the intensive care unit.

Fiberoptic bronchoscopy is a valuable tool in the intensive care unit. The procedure may be an integral part of airway management and has diagnostic and treatment capabilities. Demonstrated expertise is necessary to perform the procedure safely and effectively. This expertise may be particularly important when faced with a complex patient who presents with airway management problems or significant hemoptysis.

Sarcoidosis and its ocular manifestations.

BACKGROUND: Sarcoidosis is a significant cause of pulmonary dysfunction and ocular morbidity. The worldwide distribution of sarcoidosis involves primarily Caucasians, however, within the United States, the disease is nearly confined to the African American population. Although genetic and environmental factors have been implicated, a definitive cause of the disease, at present, remains unknown. METHODS: A review of the epidemiology, pathogenesis, and clinical features of non-ocular and ocular sarcoidosis is presented along with current thoughts on the applicability of diagnostic studies and treatment options available for afflicted patients. RESULTS: Epithelial, non-caseating granulomas are the hallmark histological findings of sarcoidosis and can be found in virtually all body tissues. The inflammatory response is a delayed hypersensitivity (type IV) reaction with an abundance of helper T-cells (CD4+). Although pulmonary findings are most common, ocular involvement with sarcoidosis occurs in approximately 25 percent of all cases. Posterior segment inflammation occurs in upwards of 28 percent of all cases of ocular sarcoidosis and is a major cause of visual morbidity among these patients. CONCLUSIONS: Sarcoidosis should be suspected in cases of granulomatous uveitis. Laboratory studies may be corroborative but should not be considered diagnostically specific or prognostic with regard to treatment. Ocular involvement often suggests a more progressive or recalcitrant form of the disease with significant pulmonary findings that may benefit from a trial course of oral prednisone.

Effects of external Rb+ on inward rectifier K+ channels of bovine pulmonary artery endothelial cells.

Inward rectifier (IR) K+ channels of bovine pulmonary artery endothelial cells were studied using the whole-cell, cell-attached, and outside-out patch-clamp configurations. The effects of Rb+ on the voltage dependence and kinetics of IR gating were explored, with [Rb+]o + [K+]o = 160 mM. Partial substitution of Rb+ for K+ resulted in voltage-dependent reduction of inward currents, consistent with Rb+ being a weakly permeant blocker of the IR. In cells studied with a K(+)-free pipette solution, external Rb+ reduced inward IR currents to a similar extent at large negative potentials but block at more positive potentials was enhanced. In outside-out patches, the single-channel i-V relationship was approximately linear in symmetrical K+, but rectified strongly outwardly in high [Rb+]o due to a reduced conductance for inward current. The permeability of Rb+ based on reversal potential, Vrev, was 0.45 that of K+, whereas the Rb+ conductance was much lower, 0.034 that of K+, measured at Vrev-80 mV. The steady state voltage-dependence of IR gating was determined in Rb(+)-containing solutions by applying variable prepulses, followed by a test pulse to a potential at which outward current deactivation was observed. As [Rb+]o was increased, the half-activation potential, V1/2, changed less than Vrev. In high [K+]o solutions V1/2 was Vrev-6 mV, while in high [Rb+]o V1/2 was Vrev + 7 mV. This behavior contrasts with the classical parallel shift of V1/2 with Vrev in K+ solutions. Steady state IR gating was less steeply voltage-dependent in high [Rb+]o than in K+ solutions, with Boltzmann slope factors of 6.4 and 4.4 mV, respectively. Rb+ decreased (slowed) both activation and deactivation rate constants defined at V1/2, and decreased the steepness of the voltage dependence of the activation rate constant by 42%. Deactivation of IR channels in outside-out patches was also slowed by Rb+. In summary, Rb+ can replace K+ in setting the voltage-dependence of IR gating, but in doing so alters the kinetics.

Advances in patient care management: the NRCU.

The noninvasive respiratory care unit has become an important advance in patient management. The NRCU allows for better use of special-care beds and represents a more cost-effective approach to the care of a number of ventilator-dependent patients or other respiratory patients. This article describes the NRCU, discusses clinical experiences and focuses on practical issues related to patient management in the NRCU.

The noninvasive respiratory care unit. Patterns of use and financial implications.

Clinical, socioeconomic, and ethical dilemmas have prompted reevaluation of traditional methods of providing intensive care. Six years ago, we established a noninvasive respiratory care unit (NRCU) for selected patients in need of intensive respiratory monitoring and therapy, particularly those requiring prolonged mechanical ventilation. One impetus for the formation of the NRCU was the expectation that it might prove to be a less costly alternative to the intensive care unit (ICU) for selected patients. We reviewed data from all patients admitted to the NRCU from July 1, 1987 through June 30, 1988 to identify characteristics of the patient population and to evaluate potential cost savings. During one year of operation, 136 patients were admitted to the unit, 107 of whom were mechanically ventilated. Overall, hospital costs for these patients exceeded payments by $1,519,477. Losses were greatest for mechanically ventilated patients and those for whom Medicare or Medicaid were the primary payors. Daily costs of care for mechanically ventilated patients were $1,976 lower in the NRCU than in the medical intensive care unit (MICU). We conclude that the NRCU represents a cost-effective approach to the care of substantial numbers of patients requiring specialized respiratory care.