James M. Bailey

Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression

Skeletal muscle atrophy is a debilitating response to starvation and many systemic diseases including diabetes, cancer, and renal failure. We had proposed that a common set of transcriptional adaptations underlie the loss of muscle mass in these different states. To test this hypothesis, we used cDNA microarrays to compare the changes in content of specific mRNAs in muscles atrophying from different causes. We compared muscles from fasted mice, from rats with cancer cachexia, streptozotocin‐induced diabetes mellitus, uremia induced by subtotal nephrectomy, and from pair‐fed control rats. Although the content of >90% of mRNAs did not change, including those for the myofibrillar apparatus, we found a common set of genes (termed atrogins) that were induced or suppressed in muscles in these four catabolic states. Among the strongly induced genes were many involved in protein degradation, including polyubiquitins, Ub fusion proteins, the Ub ligases atrogin‐1/MAFbx and MuRF‐1, multiple but not all subunits of the 20S proteasome and its 19S regulator, and cathepsin L. Many genes required for ATP production and late steps in glycolysis were down‐regulated, as were many transcripts for extracellular matrix proteins. Some genes not previously implicated in muscle atrophy were dramatically up‐regulated (lipin, metallothionein, AMP deaminase, RNA helicase‐related protein, TG interacting factor) and several growth‐related mRNAs were down‐regulated (P311, JUN, IGF‐1‐BP5). Thus, different types of muscle atrophy share a common transcriptional program that is activated in many systemic diseases.—Lecker, S. H., Jagoe, R. T., Gilbert, A., Gomes, M., Baracos, V., Bailey, J., Price, S. R., Mitch, W. E., Goldberg, A. L. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression.—Stewart H. Lecker, R. Thomas Jagoe, Alexander Gilbert, Marcelo Gomes, Vickie Baracos, James Bailey, S. Russ Price, William E. Mitch, Alfred L. Goldberg Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 18, 39–51 (2004)

Efficacy and Safety of Milrinone in Preventing Low Cardiac Output Syndrome in Infants and Children After Corrective Surgery for Congenital Heart Disease

Background—Low cardiac output syndrome (LCOS), affecting up to 25% of neonates and young children after cardiac surgery, contributes to postoperative morbidity and mortality. This study evaluated the efficacy and safety of prophylactic milrinone in pediatric patients at high risk for developing LCOS. Methods and Results—The study was a double-blind, placebo-controlled trial with 3 parallel groups (low dose, 25-&mgr;g/kg bolus over 60 minutes followed by a 0.25-&mgr;g/kg per min infusion for 35 hours; high dose, 75-&mgr;g/kg bolus followed by a 0.75-&mgr;g/kg per min infusion for 35 hours; or placebo). The composite end point of death or the development of LCOS was evaluated at 36 hours and up to 30 days after randomization. Among 238 treated patients, 25.9%, 17.5%, and 11.7% in the placebo, low-dose milrinone, and high-dose milrinone groups, respectively, developed LCOS in the first 36 hours after surgery. High-dose milrinone significantly reduced the risk the development of LCOS compared with placebo, with a relative risk reduction of 55% (P =0.023) in 238 treated patients and 64% (P =0.007) in 227 patients without major protocol violations. There were 2 deaths, both after infusion of study drug. The use of high-dose milrinone reduced the risk of the LCOS through the final visit by 48% (P =0.049). Conclusions—The use of high-dose milrinone after pediatric congenital heart surgery reduces the risk of LCOS.

Serum β-2 Microglobulin Levels Predict Mortality in Dialysis Patients: Results of the HEMO Study

In the randomized Hemodialysis (HEMO) Study, chronic high-flux dialysis, as defined by higher beta-2 microglobulin (beta(2)M) clearance, compared with low-flux dialysis did not significantly alter all-cause mortality in the entire cohort but was associated with lower mortality in long-term dialysis patients. This analysis examined the determinants of serum beta(2)M levels and the associations of serum beta(2)M levels or dialyzer beta(2)M clearance with mortality. In a multivariable regression model that examined 1704 patients, baseline residual kidney urea clearance and dialyzer beta(2)M clearance were strong predictors of predialysis serum beta(2)M levels at 1 mo of follow-up, with regression coefficients of -7.21 (+/-0.69 SE) mg/L per ml/min per 35 L urea volume (P < 0.0001) and -1.94 (+/-0.30) mg/L per ml/min (P < 0.0001),respectively. In addition, black race and baseline years on dialysis correlated positively whereas age, diabetes, serum albumin, and body mass index correlated negatively with serum beta(2)M levels (P < 0.05). In time-dependent Cox regression models, mean cumulative predialysis serum beta(2)M levels but not dialyzer beta(2)M clearance were associated with all-cause mortality (relative risk = 1.11 per 10-mg/L increase in beta(2)M level; 95% confidence interval 1.05 to 1.19; P = 0.001), after adjustment for residual kidney urea clearance and number of prestudy years on dialysis. This association is supportive of the potential value of beta(2)M as a marker to guide chronic hemodialysis therapy.

Effects of High-Flux Hemodialysis on Clinical Outcomes: Results of the HEMO Study

Among the 1846 patients in the HEMO Study, chronic high-flux dialysis did not significantly affect the primary outcome of the all-cause mortality (ACM) rate or the main secondary composite outcomes, including the rates of first cardiac hospitalization or ACM, first infectious hospitalization or ACM, first 15% decrease in serum albumin levels or ACM, or all non-vascular access-related hospitalizations. The high-flux intervention, however, seemed to be associated with reduced risks of specific cardiac-related events. The relative risks (RR) for the high-flux arm, compared with the low-flux arm, were 0.80 [95% confidence interval (CI), 0.65 to 0.99] for cardiac death and 0.87 (95% CI, 0.76 to 1.00) for the composite of first cardiac hospitalization or cardiac death. Also, the effect of high-flux dialysis on ACM seemed to vary, depending on the duration of prior dialysis. This report presents secondary analyses to further explore the relationship between the flux intervention and the duration of dialysis with respect to various outcomes. The patients were stratified into a short-duration group and a long-duration group, on the basis of the mean duration of dialysis of 3.7 yr before randomization. In the subgroup that had been on dialysis for >3.7 yr, randomization to high-flux dialysis was associated with lower risks of ACM (RR, 0.68; 95% CI, 0.53 to 0.86; P = 0.001), the composite of first albumin level decrease or ACM (RR, 0.74; 95% CI, 0.60 to 0.91; P = 0.005), and cardiac deaths (RR, 0.63; 95% CI, 0.43 to 0.92; P = 0.016), compared with low-flux dialysis. No significant differences were observed in outcomes related to infection for either duration subgroup, however, and the trends for beneficial effects of high-flux dialysis on ACM rates were considerably weakened when the years of dialysis during the follow-up phase were combined with the prestudy years of dialysis in the analysis. For the subgroup of patients with <3.7 yr of dialysis before the study, assignment to high-flux dialysis had no significant effect on any of the examined clinical outcomes. These data suggest that high-flux dialysis might have a beneficial effect on cardiac outcomes. Because these results are derived from multiple statistical comparisons, however, they must be interpreted with caution. The subgroup results that demonstrate that patients with different durations of dialysis are affected differently by high-flux dialysis are interesting and require further study for confirmation.

Impact of Dialysis Dose and Membrane on Infection-Related Hospitalization and Death: Results of the HEMO Study

Infection is the second most common cause of death among hemodialysis patients. A predefined secondary aim of the HEMO study was to determine if dialysis dose or flux reduced infection-related deaths or hospitalizations. The effects of dialysis dose, dialysis membrane, and other clinical parameters on infection-related deaths and first infection-related hospitalizations were analyzed using Cox regression analysis. Among the 1846 randomized patients (mean age, 58 yr; 56% female; 63% black; 45% with diabetes), there were 871 deaths, of which 201 (23%) were due to infection. There were 1698 infection-related hospitalizations, yielding a 35% annual rate. The likelihood of infection-related death did not differ between patients randomized to a high or standard dose (relative risk [RR], 0.99 [0.75 to 1.31]) or between patients randomized to high-flux or low-flux membranes (RR, 0.85 [0.64 to 1.13]). The relative risk of infection-related death was associated (P < 0.001 for each variable) with age (RR, 1.47 [1.29 to 1.68] per 10 yr); co-morbidity score (RR, 1.46 [1.21 to 1.76]), and serum albumin (RR, 0.19 [0.09 to 0.41] per g/dl). The first infection-related hospitalization was related to the vascular access in 21% of the cases, and non-access-related in 79%. Catheters were present in 32% of all study patients admitted with access-related infection, even though catheters represented only 7.6% of vascular accesses in the study. In conclusion, infection accounted for almost one fourth of deaths. Infection-related deaths were not reduced by higher dose or by high flux dialyzers. In this prospective study, most infection-related hospitalizations were not attributed to vascular access. However, the frequency of access-related, infection-related hospitalizations was disproportionately higher among patients with catheters compared with grafts or fistulas.

Predicting and treating coagulopathies after cardiopulmonary bypass in children.

Coagulopathies in children after cardiopulmonary bypass (CPB) are complex.There are very limited data correlating coagulation tests with postoperative bleeding. We evaluated coagulation changes after CPB and after the administration of coagulation products to 75 children. Baseline coagulation tests were obtained and repeated after protamine administration, after transfusion of individual coagulation products, and on arrival in the intensive care unit (ICU). Regression analysis demonstrated no baseline coagulation test to predict postoperative chest tube drainage. Weight and duration of CPB were determined to be the only predictors of bleeding. Further analyses demonstrated that children <8 kg had more bleeding and required more coagulation products than children >8 kg. Postprotamine platelet count and fibrinogen level correlated independently with 24-h chest tube drainage in children <8 kg, whereas postprotamine platelet count and thrombelastographic values did so in patients weighing >8 kg. Platelet administration alone was found to restore effective hemostasis in many patients. With ongoing bleeding, cryoprecipitate improved coagulation parameters and limited blood loss. Fresh-frozen plasma administration after platelets worsened coagulation parameters and was associated with greater chest tube drainage and more coagulation product transfusions in the ICU. Objective data to guide post-CPB component therapy transfusion in children are suggested. Implications: Children <8 kg can be expected to have more severe coagulopathies, require more coagulation product transfusions, and bleed more after cardiopulmonary bypass. Correlations between coagulation tests and postoperative chest tube drainage are defined. Platelets and, if necessary, cryoprecipitate optimally restore hemostasis. Fresh-frozen plasma offers no benefits in correcting postcardiopulmonary bypass coagulopathies in children. (Anesth Analg 1997;85:1196-202)

Context-sensitive half-times and other decrement times of inhaled anesthetics

The length of anesthetic administration influences the rate at which concentrations of anesthetics decrease after their discontinuation.This is true for both intravenous (IV) and inhaled anesthetics. This has been explored in detail for IV anesthetics using computer simulation to calculate context-sensitive half-times (the time needed for a 50% decrease in anesthetic concentration) and other decrement times (such as the times needed for 80% or 90% decreases in anesthetic concentration). However, decrement times have not been reported for inhaled anesthetics. In this report, published pharmacokinetic parameters and computer simulation were used to compare the context-sensitive half-times and the 80% and 90% decrement times of the expected central nervous system concentrations for enflurane, isoflurane, sevoflurane, and desflurane. The context-sensitive half-times for all four anesthetics are small (<5 min) and do not increase significantly with increasing duration of anesthesia. The 80% decrement times of both sevoflurane and desflurane are also small (<8 min) and do not increase significantly with duration of anesthesia. However, the 80% decrement times of isoflurane and enflurane increase significantly after approximately 60 min of anesthesia, reaching plateaus of approximately 30 and 35 min. The 90% decrement time of desflurane increased slightly from 5 min after 30 min of anesthesia to 14 min after 6 h of anesthesia. It remained significantly less than the 90% decrement times of sevoflurane, isoflurane, and enflurane, which reached values of 65 min, 86 min, and 100 min, respectively, after 6 h of anesthesia. Implications: The major differences in the rates at which desflurane, sevoflurane, isoflurane, and enflurane are eliminated occur in the final 20% of the elimination process. (Anesth Analg 1997;85:681-6)

The Pharmacokinetics of Milrinone in Pediatric Patients after Cardiac Surgery

BACKGROUND Milrinone has been shown to increase cardiac output in children after cardiac surgery, but pharmacokinetic analysis has not been used to identify effective dose regimens. The purpose of this study was to characterize the pharmacokinetics of milrinone in infants and children and to apply the results to the issue of dosing. METHODS Twenty children were studied after they underwent repair of congenital cardiac defects. Control hemodynamic measurement was made after the children were separated from cardiopulmonary bypass, and each patient was given a loading dose of 50 microg/kg progressively in 5 min. Hemodynamic measurements were recorded again at the end of the loading dose and when a blood sample was taken to determine milrinone plasma concentrations. Further blood samples were taken during the next 16 h for milrinone plasma concentration analysis. The pharmacokinetics of milrinone were analyzed using the population pharmacokinetic program NONMEM. RESULTS The loading dose of milrinone resulted in a mean decrease in mean blood pressure of 12% and a mean increase in cardiac index of 18% at a mean peak plasma concentration of 235 ng/ml. The pharmacokinetics of milrinone were best described by a three-compartment model. In the optimal model, all volumes and distribution clearances were proportional to weight, and weight-normalized elimination clearance was proportional to age; ie., Cl1 = 2.5 x weight x (1 + 0.058 x age) where Cl1 is expressed as ml/min, and the units of weight and age are kg and months, respectively. CONCLUSIONS A loading dose of 50 microg/kg effectively increases cardiac index in children after cardiac surgery. Simulations indicate that the peak plasma concentration can be maintained by following the loading dose of 50 microg/kg with an infusion of approximately 3 microg x kg(-1) x min(-1) for 30 min and then a maintenance infusion, which may require adjustment for age.

Pharmacokinetics of Aprotinin in Preoperative Cardiac Surgical Patients

Background:Aprotinin, a polypeptide protease inhibitor, reduces bleeding and transfusion requirements during cardiac surgery. To investigate aprotinins pharmacokinetics, we administered therapeutic doses to patients scheduled to undergo cardiac surgery. Methods:Preoperative doses of 500,000 and 1,000,000 kallikrein inhibitor units (KIU) were administered as an infusion over 30 min to 28 patients, and plasma concentrations were measured for 48 h. Aprotinin concentrations were determined using a sandwich-enzyme-linked immunosorbent assay. A three-compartment model was fit to the measured aprotinin concentrations using extended nonlinear least-squares regression. Results:Plasma aprotinin concentrations at the end of the 30-min infusion were 147 ± 61 KIU/ml for the 1,000,000-KIU dose and 60 ± 19 KIU/ml for the 500,000-KIU dose. Elimination clearance was 35.5 ml/min, and volume of distribution at steady state was 26.5 1. Conclusions:A 2,000,000-KIU dose is needed to produce the plasma concentration of 200 KIU/ml associated with kallikrein inhibition. Plasma concentrations in excess of 50 KIU/ml, the concentration required to inhibit plasma, can be achieved by a significantly smaller dose. Based on the derived pharmacokinetic parameters, an infusion model was developed to appropriately administer and maintain effective plasma concentrations of aprotinin, depending on the plasma concentration desired and the target proteases to be inhibited.

Functional Maturity of the Coagulation System in Children: An Evaluation Using Thrombelastography

There are quantitative deficiencies in the coagulation system for at least the first 6 mo of life.Clinical experience, however, does not indicate an increased risk of excessive bleeding during surgical procedures. Thrombelastography, a test providing a functional evaluation of coagulation, was used to assess the hemostatic system of pediatric patients under 2 yr of age. Thrombelastographic data were obtained from 237 healthy pediatric patients less than 2 yr of age undergoing elective noncardiac surgery. Five groups were distinguished: under 30 days, 1-3 mo, 3-6 mo, 6-12 mo, and 12-24 mo. Thrombelastography revealed no defects in coagulation when these groups were compared to each other or to adults, indicating a functionally intact hemostatic process even in neonates. Indeed, children less than 12 mo of age were found to initiate and develop clot faster than adults, with the coagulation process slowing to adult rates after 1 yr of age. In addition to defining functional integrity, our data represents a set of pediatric control thrombelastographic values that have not been previously reported and that may become important in understanding coagulation changes that accompany disease states and surgery in pediatric patients. (Anesth Analg 1997;84:745-8)