Effect Of Body Surface Area Research Articles

Understanding hemoglobin contribution to high-dose methotrexate disposition-population pharmacokinetics in pediatric patients with hematological malignancies.

The aim of the present study was to develop a population pharmacokinetic model for methotrexate (MTX) during high-dose treatment (HDMTX) in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) and to describe the influence of variability factors. The study included 50 patients of both sexes (aged 1-18years) who received 3 or 5g/m2 of HDMTX. A nonlinear mixed effect modeling approach was applied for data analysis. Parameter estimation was performed by first-order conditional estimation method with interaction (FOCEI), whereas stepwise covariate modeling was used to assess variability factors. The final model is a two-compartment model that incorporates the effect of body surface area and the influence of hemoglobin and serum creatinine on MTX clearance (CL). Population pharmacokinetic values for a typical subject were estimated at 5.75 L/h/m2 for clearance (CL), 21.3 L/m2 for volume of the central compartment (V1), 8.2 L/m2 for volume of the peripheral compartment (V2), and 0.087 L/h/m2 for intercompartmental clearance (Q). According to the final model, MTX CL decreases with increasing serum creatinine, whereas a positive effect was captured for hemoglobin. A difference of almost 32% in MTX CL was observed among patients' hemoglobin values reported in the study. The developed population pharmacokinetic model can contribute to the therapy optimization during HDMTX in pediatric patients with ALL and NHL. In addition to renal function and body weight, it describes the influence of hemoglobin on CL, allowing better understanding of its contribution to the disposition of HDMTX.

Reference data for left ventricular filling and atrial function in children using cardiovascular magnetic resonance

BackgroundDiastolic dysfunction is associated with morbidity and mortality in multiple pediatric disease processes. Cardiovascular magnetic resonance (CMR) provides a non-invasive method of studying left ventricular (LV) diastolic dysfunction through the assessment of LV filling curves and left atrial (LA) volume and function. However, there are no normative data for LV filling curves and the standard method is time-intensive. This study aims to compare an alternate, more rapid method of obtaining LV filling curves to standard methodology and report normative CMR diastolic function data for LV filling curves and LA volumes and function. MethodsNinety-six healthy pediatric subjects (14.3 ± 3.4 years) with normal CMR defined by normal biventricular size and systolic function without late gadolinium enhancement were included. LV filling curves were generated by removing basal slices without myocardium present throughout the cardiac cycle and apical slices with poor endocardial delineation (compressed method), then re-generated including every phase of myocardium from apex to base (standard method). Indices of diastolic function included peak filling rate and time to peak filling. Systolic metrics included peak ejection rate and time to peak ejection. Both peak ejection and peak filling rates were indexed to end-diastolic volume. LA maximum, minimum and pre-contraction volumes were calculated using a biplane method. Inter-and intra-observer variability were assessed with intraclass correlation coefficient. Multivariable linear regression was used to assess the effects of body surface area (BSA), gender and age on metrics of diastolic function. ResultsBSA had the largest effect on LV filling curves. Normal LV filling data are reported for both compressed and standard methods. The time to perform the compressed method was significantly shorter than the standard method (median 6.1 min vs. 12.5 min, p < 0.001). Both methods had strong to moderate correlation for all metrics. Intra-observer reproducibility was moderate to high for all LV filling and LA metrics except for time to peak ejection and peak filling. ConclusionsWe report reference values for LV filling metrics and LA volumes. The compressed method is more rapid and produces similar results to standard methodology, which may facilitate the use of LV filling in clinical CMR reporting.

Effect of Body Surface Area on Severe Osteoporotic Fractures: A Study of Osteoporosis in Changsha China.

Clinical vertebral fractures and femoral neck fractures are severe osteoporotic fractures that increase morbidity and mortality. Anthropometric variables are associated with an increased risk of osteoporotic fractures, but it is not clear whether body surface area (BSA) has an effect on clinically severe osteoporotic fractures. The study included total of 3,694 cases of clinical vertebral fractures and femoral neck fractures (2,670 females and 1,024 males) and 3,694 controls without fractures who were matched with the cases by sex and age. There was a significant positive correlation between BSA and bone mineral density (BMD) in female and male fracture patients (females: r = 0.430–0.471, P < 0.001; males: r = 0.338–0.414, P < 0.001). There was a significant systematic increase in BMD in both genders at various skeletal sites, grouped by BSA quartile. The osteoporosis rates of the lumbar spine (97.9%), femoral neck (92.4%) and total hip (87.1%) in the female Q1 group were significantly higher than those in the Q4 group (P < 0.001), which were 80.0%, 57.9% and 36.9%, respectively, in the Q4 group; the osteoporosis rates of the lumbar spine, femoral neck, and total hip were 53.9%, 59.4%, and 36.3% in the male Q1 group, and 15.2%, 21.9%, and 7.03% in the Q4 group, which were significantly lower than those in the Q1 group (P < 0.001). In age-adjusted Cox regression models, the risk of fracture in the remaining three groups (Q2, Q3, and Q4) for weight, BMI, and BSA for both genders, compared with the highest quartile (Q1 by descending quartile stratification) were significantly higher. In models adjusted for age and BMD, only men in the BSA Q3 (HR = 1.55, 95% CI = 1.09–2.19) and BSA Q4 groups (HR = 1.41, 95% CI = 1.05–1.87) had significantly higher fracture risks. In models adjusted for age, height, weight, BMI, and BSA, low BMD was the greatest fracture risks for both sexes. Our results showed that BSA was closely related to BMD, prevalence of osteoporosis, and fracture risk, and that a decline in BSA may be a new potential risk factor for osteoporotic fractures in Chinese men.

Obesity Related Glomerulopathy in Adolescent Women: The Effect of Body Surface Area.

Adolescent obesity, a risk factor for cardiorenal morbidity in adulthood, has reached epidemic proportions. Obesity-related glomerulopathy (ORG) has an early reversible stage of hyperfiltration. Age-appropriate formulae for eGFR, which are standardized to ideal body surface area (BSA) and provide assessment of kidney function in ml/min/1.73 m2, may underestimate prevalence of early ORG. We investigated whether adjusting eGFR to actual BSA more readily identifies early ORG. We studied a cohort of 22,417 young individuals, aged 12-21 years, from a New York metropolitan multi-institutional electronic health records clinical database. eGFR was calculated in two ways: BSA-standardized eGFR, and absolute eGFR. Hyperfiltration was defined above a threshold of 135 ml/min per 1.73 m2 or 135 ml/min, respectively. The prevalence of hyperfiltration according to each formula was assessed in parallel to creatinine clearance. Serum creatinine values and hyperfiltration prevalence according to BSA-standardized eGFR were similar, 13%-15%, across body mass index (BMI) groups. The prevalence of hyperfiltration determined by absolute eGFR differed across BMI groups: underweight, 2%; normal weight, 6%; overweight, 17%; and obese, 31%. This trend paralleled the rise in creatinine clearance across BMI groups. Absolute eGFR more readily identifies early ORG than the currently used formulae, which are adjusted to a standardized BSA and are not representative of current population BMI measures. Using absolute eGFR in clinical practice and research may improve the ability to identify, intervene, and reverse early ORG, which has great importance with increasing obesity rates.

Effect of body surface area and gender on wall thickness thresholds in hypertrophic cardiomyopathy.

BackgroundFamily screening for hypertrophic cardiomyopathy (HCM) is based on genetic testing and clinical evaluation (maximal left ventricular wall thickness (MWT) ≥15 mm, or ≥13 mm in first-degree relatives of HCM patients). The aim of this study was to assess the effect of gender and body size on diagnosis of HCM and prediction of clinical outcome.MethodsThis study includes 199 genotype-positive subjects (age 44 ± 15 years, 50% men) referred for cardiac screening. Gender-specific reference values for MWT indexed by body surface area (BSA), height and weight were derived from 147 healthy controls. Predictive accuracy of each method for HCM-related events was assessed by comparing areas under the receiver operating characteristic curves (AUC).ResultsMen had a higher absolute, but similar BSA- and weight-indexed MWT compared with women (14.0 ± 3.9 mm vs 11.5 ± 3.8 mm, p < 0.05; 6.8 ± 2.1 mm/m2 vs 6.6 ± 2.4 mm/m2; 0.17 ± 0.06 mm/kg vs 0.17 ± 0.06 mm/kg, both p > 0.05). Applying BSA- and weight-indexed cut-off values decreased HCM diagnoses in the study group (48% vs 42%; 48% vs 39%, both p < 0.05), reclassified subjects in the largest, lightest and heaviest tertiles (≥2.03 m2: 58% vs 45%; ≤70 kg: 37% vs 46%; ≥85 kg: 53% vs 25%, all p < 0.05) and improved predictive accuracy (AUC 0.76 [95% CI 0.69–0.82] vs 0.78 [0.72–0.85]; and vs 0.80 [0.74–0.87]; both p < 0.05).ConclusionsIn genotype-positive subjects referred for family screening, differences in MWT across gender are mitigated after indexation by BSA or weight. Indexation decreases the prevalence of HCM, particularly in larger men, and improves the predictive accuracy for HCM-related events.

Population pharmacokinetics of pevonedistat alone or in combination with standard of care in patients with solid tumours or haematological malignancies.

AimsA population pharmacokinetic (PK) analysis was conducted to quantify the impact of patient‐specific and concurrent medication factors on pevonedistat PK.MethodsData were pooled from 6 clinical studies consisting of 335 patients with solid tumours or haematological malignancies administered pevonedistat alone or in combination with azacitidine, docetaxel, carboplatin + paclitaxel, or gemcitabine. Model development and covariate analysis followed standard methods. Parameters and bootstrap 95% confidence intervals were estimated using nonlinear mixed‐effects modelling. The final model was evaluated using visual predictive checks and other goodness‐of‐fit criteria.ResultsA linear 2‐compartment model best described pevonedistat PK. The final model included the effect of body surface area (BSA) on clearance (CL and Q) and volume of distribution of pevonedistat, effect of concomitantly administered carboplatin + paclitaxel on CL, and effect of albumin on Q. Race, sex, age, tumour type (haematological vs solid), mild or moderate renal impairment (creatinine clearance ≥30 mL/min), or mild hepatic impairment, had no impact on pevonedistat PK.ConclusionsThe clinical PK profile of pevonedistat is comparable in patients with solid tumours or haematological malignancies. All PK parameters exhibited ≥20% change over the observed BSA range (1.38–3 m2) with CL ranging from 75.5 to 208% of the reference value, with simulations supporting BSA‐based dosing to minimize interindividual variability in drug exposures. Concurrent administration of carboplatin + paclitaxel decreased pevonedistat CL by approximately 44%, while coadministration with azacitidine, gemcitabine or docetaxel did not alter pevonedistat CL. No other factors were identified as influencing pevonedistat PK.

97 Six Months of Exercise Training and Aerobic Capacity in Well-Healed Burn Survivors: Effect of Body Surface Area Burned

Aerobic exercise is an important component towards the full rehabilitation of burn survivors, yet aerobic capacity is reduced in this population. No studies have examined the benefits of long-term aerobic exercise training in well-healed burn survivors, particularly stratified by the severity of the burn injury. This study tested the hypothesis that a community-based 6-month exercise training regimen would improve aerobic capacity in burn survivors, with the magnitude of this improvement being influenced by body surface area (BSA) burned. Eleven unburned control subjects (34±8 y), 12 low BSA burn survivors (38±14 y; 27±7% BSA burned), and 11 high BSA burn survivors (39±12 y; 58±16% BSA burned) participated in a 6-month community-based aerobic exercise training regimen. Burn survivors were assessed a minimum of 2 years after the injury. Both prior to and after this exercise regimen, subjects performed steady-state cycle exercise (50 and 75 Watts) and two graded maximal cycle exercise tests, where maximal oxygen uptake (VO2max) was obtained. For both pre- and post-training periods, the greater of the two VO2max values was selected and analyzed. Exercise training improved VO2max in all groups (Control: 2.94±0.76 to 3.19±0.61 L/min; low burned: 2.24±0.52 to 2.48±0.54 L/min; high burned: 2.47±0.50 to 2.54±0.48 L/min; P<0.001 main effect of pre/post training), without any differences in the magnitude of the improvement between groups (P=0.27 for the interaction). Perhaps equally important was a ~10 beat per min lowering of heart rate post-exercise training in all groups during steady-state exercise of 50 and 75 Watts, demonstrating lower cardiovascular stress post-training at workloads that approximate activities of daily living (e.g., ~2 to 4 METS). These data demonstrate that well-healed burn survivors have the capability to appropriately improve their aerobic capacity through an aggressive long-term exercise training regimen. Counter to our hypothesis, there was no difference between the magnitude of the improvements in VO2max and the percent BSA burned, though the high burn group had an appreciably lower mean elevation in VO2max post-training. As a population, burn survivors have a reduced aerobic capacity relative to unburned peers, with these lower values being related to higher morbidity and all-cause mortality. Thus, without an intervention to improve aerobic capacity, burn survivors will experience the negative sequelae associated with a sedentary lifestyle. The present data demonstrate that burn survivors generally have the capability to improve their aerobic capacity via a long-term aerobic exercise regimen. Funded by: NIH - GM68865

Evaluation of osimertinib efficacy according to body surface area and body mass index in patients with non-small cell lung cancer harboring an EGFR mutation: A prospective observational study.

BackgroundOsimertinib is recommended for non‐small cell lung cancer (NSCLC) patients with EGFR mutation; however, it is unclear whether body size variables affect the efficacy of osimertinib in such patients. This study assessed the potential effect of body surface area (BSA) and body mass index (BMI) on osimertinib chemotherapy in patients with T790M‐positive advanced NSCLC who progress on prior EGFR‐tyrosine kinase inhibitors (TKIs).MethodsWe conducted a prospective observational cohort study. Median BSA and BMI were used as cut‐off values to evaluate the impact of body size variables on osimertinib chemotherapy.ResultsThe median BSA and BMI of 47 patients were 1.50 m2 and 21.5 kg/m2, respectively. Clinical outcomes did not significantly differ between the high and low BSA groups, with response rates of 59.1% and 56.0% (P = 0.83) and progression‐free survival (PFS) of 7.6 and 9.1 months (P = 0.69), respectively. Similarly, there were no significant differences between the high and low BMI groups relative to response rates, which were 60.8% and 54.1% (P = 0.64), respectively, and PFS, which was 7.6 months in both groups (P = 0.38). No significant differences were observed among toxicity profiles in relation to BSA or BMI. Multivariate analysis identified better performance status, young age, and EGFR exon 19 deletion as independent favorable predictors of PFS.ConclusionThe efficacy of osimertinib does not significantly vary relative to body size variables of patients with T790M‐positive NSCLC who progress on prior EGFR‐TKIs.

Normal Pediatric Values of the Subcostal Tricuspid Annular Plane Systolic Excursion (S-TAPSE) and Its Value in Pediatric Pulmonary Hypertension

BackgroundThe clinical value of determination of right ventricular (RV) function in adults using echocardiographic determination of the subcostal tricuspid annular plane systolic excursion (S-TAPSE) has previously been reported. We aim to provide representative, normal reference values for S-TAPSE in the pediatric age group. Moreover, validation of abnormal S-TAPSE values in children with impaired RV function, such as pulmonary hypertension (PH), is intended. MethodsWe propose a prospective echocardiographic study in 658 healthy children and in 27 children with PH (age: 1 day to 18 years; BSA 0.2-2.0 m2). We correlated the effects of body surface area (BSA) on S-TAPSE values of our healthy subjects and children with PH. S-TAPSE values were compared with apically derived TAPSE values. ResultsS-TAPSE values ranged from a mean of 0.65 ± 0.16 cm in healthy neonates to 1.79 ± 0.33 cm in 18-year-old healthy adolescents. S-TAPSE values increased with increasing age (P = 0.841, P < 0.001), body weight (P = 0.852, P < 0.001), body length (P = 0.846, P < 0.001), and BSA (P = 0.851, P < 0.001) in a nonlinear way in our healthy patients group. No difference in healthy male and female patients could be observed. In our 27 patients with PH (age range: 0.6 to 15.7 years) the median BSA specific S-TAPSE z-score ranged from –3.24 to 1.10, depending on restraint of RV function. ConclusionThe provided S-TAPSE normal reference values and z-scores may assist to identify children with impaired RV function. Abnormal S-TAPSE values will help to identify impaired RV function in pediatric patients with PH.

Longitudinal Assessment of the Doppler-Estimated Maximum Gradient in Patients With Congenital Valvar Aortic Stenosis Pre- and Post-Balloon Valvuloplasty.

Aortic stenosis has been reported to manifest a slow rate of progression in mild disease, with a greater likelihood of progression in patients with moderate-severe disease. The natural history of the Doppler-estimated maximum gradient (DEMG) in patients after balloon aortic valvuloplasty (BAVP) has not previously been studied on a large scale. A retrospective review was performed of 360 patients from 1984 to 2012 with aortic stenosis, providing a total of 2059 echocardiograms both before and after BAVP. Patients were excluded if they had an intervention within the first 30 days of life. The relationships between the aortic stenosis DEMG and several predictors (age at initial study, body surface area, valve morphology, and initial DEMG) were explored using linear mixed effect models. Patients with a unicommissural aortic valve had a significantly higher rate of progression compared with those with a bicommissural aortic valve (0.81 and 0.45 mm Hg/year; P<0.001). The median rate of progression in the post-BAVP group was significantly lower than the median pre-BAVP rate of progression (n=34; pre-BAVP 3.97 [1.69-8.7] mm Hg/year; post-BAVP 0.40 [-1.80 to 3.88] mm Hg/year; P<0.008). When adjusted for body surface area, there was no significant increase in the DEMG (-0.03 mm Hg/m2 per year; P<0.001). There is a statistically significant increase in the DEMG over time in patients with aortic stenosis. After balloon dilation, the DEMG rate of change is reduced compared with that pre-dilation. Given the effect of body surface area on DEMG progression, more frequent observation should be made during periods of rapid somatic growth.

Abstract B148: Population pharmacokinetics (PK) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) administered alone or in combination with azacitidine in patients (pts) with solid or hematologic malignancies

Abstract Introduction: Pevonedistat is a first-in-class small molecule inhibitor of NAE that is currently in phase 1b clinical development across multiple solid tumors and in acute myeloid leukemia (AML). Here we report a population modeling analysis to describe pevonedistat IV PK in cancer pts and identify potential predictors of interpatient variability in pevonedistat exposures when given alone or combined with azacitidine. Methods: Plasma concentration-time data were analyzed using nonlinear mixed effects modeling (NONMEM 7.2). Two- and 3-compartment linear disposition with zero-order input models were tested. Subsequently, effects of selected demographic (age, sex, race, and body size) and physiologic (hepatic transaminases, bilirubin, blood parameters, and creatinine clearance [CRCL]) covariates were evaluated. First Order Conditional Estimation method with log transform-both-sides was used. Model goodness-of-fit and performance (visual predictive check and nonparametric bootstrapping) were also assessed. Results: A total of 250 pts (64% male; 80% white) from 5 completed or ongoing phase 1/1b dose-escalation clinical studies contributed 2882 observations. Of these, 42% were 65 yrs or older and 18% were 75 yrs or older. Half of pts had normal renal function, while 34% and 17% had mild (CRCL 60-89 mL/min) to moderate (CRCL 30-59 mL/min) renal impairment, respectively. Data were described by a 2-compartment PK model parameterized in terms of systemic clearance (CL), intercompartmental clearance (Q), and central (Vc) and peripheral (Vp) volumes of distribution with associated between-subject variability (BSV). Terms describing correlations between BSV for CL, Q, and Vp were included. Body size was described as an allometric function with the effect of body surface area (BSA, range 1.38-3.00 m2) on all parameters. Age (range 19-90 yrs) on CL was included as a power function normalized by the reference age of 65 yrs. Categorical covariates (sex and race) were modeled to estimate the proportional change in the typical value of the PK parameter. Consistent with observations of dose-proportional increases in pevonedistat exposures within each study, CL was constant across doses. Pevonedistat PK was unaffected after daily dosing with azacitidine in pts with AML. Final population mean parameter estimates (95% bootstrap confidence interval [CI]) were CL = 29.0 L/h (25.8, 32.7); Vc = 93.5 L (79.1, 110); Vp = 107 L (99.3, 115); and Q = 20.1 L/h (18.3, 22.2). Proportional residual variability was 28%. Upon exploration of patient-specific covariate effects, body size influenced CL (interindividual variability [IIV] ∼25% CV) and volume of distribution (IIV∼22% CV). Pevonedistat CL tended to gradually decrease with age (∼25% over the 30-90 yrs age range). There was no apparent effect of renal function status (CRCL &amp;gt;30 mL/min) on pevonedistat PK. Conclusions: The clinical PK profile of pevonedistat is comparable in pts with solid tumors, lymphomas, or AML. No changes were observed in the presence of azacitidine when compared to historical single-agent data. Elderly pts may have reduced pevonedistat CL; additional monitoring of these pts is recommended. Citation Format: Hélène M. Faessel, Diane R. Mould, Bruce J. Dezube, Sergio Santillana, Karthik Venkatakrishnan. Population pharmacokinetics (PK) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) administered alone or in combination with azacitidine in patients (pts) with solid or hematologic malignancies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B148.

Association Between Body Surface Area and Outcomes After Percutaneous Coronary Intervention

Obesity is a well-known risk factor for adverse cardiovascular events, but some studies suggest higher body mass index (BMI) is associated with better outcomes after ST-segment elevation myocardial infarction (STEMI). We sought to determine the effect of body surface area (BSA) on adverse events after primary percutaneous coronary intervention (PCI) for STEMI and how this relates to the reported obesity paradox theory.

Population Pharmacokinetics of Methotrexate in Egyptian Children with Lymphoblastic Leukemia

Background: Individualization of high dose regimen of methotrexate (MTX) in pediatric patients with acute lymphoblastic leukemia based on pharmacokinetic (PK) parameters can help in optimization of the dose and better control of the disease. Building up of a pharmacokinetic model can help dose optimization. Objectives: A NONMEM based population (POP) PK model has been subsequently developed to evaluate the effect of demographics as covariates to address variability in pharmacokinetics of MTX. Method: Forty one patients (24 males & 17 females) with ranges of age, body weight and height of 3 - 15 years, 13 - 54 kg and 100 - 177 cm respectively and diagnosed as acute lymphoblastic leukemia (ALL) were involved in the study. MTX was administered as i.v. infusion at a dose of 2 gm/m2 over a period of two hour and its plasma concentrations were determined primarily at 24 hr post-dose to be utilized in the building-up of PK model.The initial/prior estimates of volumes of central (V1) and peripheral compartments (V2) and clearance (CL) and inter-compartmental clearance (Q2) for MTX were extracted from literature. The inter-subject variability was estimated for V1 & CL. The influence of different covariates on model performance and parameter estimates was assessed by evaluating the difference in objective function value. The final POP PK model was validated by bootstrap re-sampling procedures (1000 runs) and the 95% confidence intervals for the estimates were calculated. Results: The POP estimates for CL, V1 and V2 were 2.18 L/h, 5.74 L and 11.2 L respectively. The inter-individual variability for the CL and V1 was 23% and 30% respectively. The covariates analysis showed effect of body surface area and sex on the CL and weight on V1. Conclusions: The POP-PK model developed adequately defines the population PK of MTX in pediatric patients with lymphoblastic leukemia. The model showed effect of body surface area and sex on clearance and weight on volume of distribution of the MTX. Further studies are required on larger number of patients with enrichment of samples for MTX concentrations. The developed PK model should be also investigated in correlation with the genotyping style of different MTX transporters that may affect MTX PK parameters.

Laterality and sex differences in tactile detection and two-point thresholds modified by body surface area and body fat ratio

Tactile detection and two-point discrimination tests are commonly used in neurological examinations. However, questions remain about the influence of both body and patient characteristics on test thresholds. The left side of the body has sometimes been reported more tactilely sensitive than the right, and females are said to be more sensitive than males. We measured tactile detection and two-point discrimination thresholds on the finger, palm, and forehead of a large sample of young adults (N = 171), examining laterality and sex differences, and the effects of body surface area (BSA) and body fat ratio (BFR). In tactile detection, there were no effects of laterality, BSA, or BFR, although females had lower thresholds than males. In two-point discrimination, there was an effect of laterality, with lower thresholds on the left side. This probably reflects hemispheric spatial processing differences. A significant BFR effect implies that subcutaneous fat affects skin deformation, but there were no effects of sex or BSA. The two-point discrimination findings differ in several respects from recent findings using grating orientation discriminations. A small positive correlation between the tasks, falling far short of test–retest reliabilities, indicates that they use largely disjoint but partially overlapping processes.

Pharmacokinetics of Dexrazoxane in Subjects With Impaired Kidney Function

Dexrazoxane is approved as a cardioprotective agent for use in female patients with breast cancer who are receiving doxorubicin. The effect of renal insufficiency on elimination is not known. The pharmacokinetics of dexrazoxane 150 mg/m(2), given as a 15-minute constant-rate intravenous infusion, were assessed in 24 men and women with varying degrees of renal function in a single-dose, open-label, parallel-group study. Blood and urine samples were measured by a validated liquid chromatography/mass spectrometry assay. Dexrazoxane pharmacokinetic parameters were derived by standard noncompartmental methods. The effect of kidney function and effect of body surface area on the pharmacokinetics of dexrazoxane were analyzed using linear and nonlinear regression in the SPSS statistical program. Dexrazoxane clearance is decreased in subjects with kidney dysfunction. Compared with normal subjects (creatinine clearance [CL(CR)] >80 mL/min), mean area under the concentration curve from time 0 to infinity (AUC(0-inf)) was 2-fold greater in subjects with moderate (CL(CR) 30-50 mL/min) to severe (CL(CR) <30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC(0-inf)) could be achieved if dosing were reduced by 50% in subjects with CL(CR) less than 40 mL/min compared with control subjects (CL(CR) >80 mL/min). Modeling study results suggested that equivalent exposure could be achieved if dosing was halved in subjects with CL(CR) less than 40 mL/min compared with controls.

Association between indices of prosthesis internal orifice size and operative mortality after isolated aortic valve replacement

The appropriate index of prosthesis internal orifice size and its effect on operative mortality after aortic valve replacement are controversial. We examined the association between several relevant indices and patient size on operative mortality. Indices examined included projected in vivo effective orifice area and geometric orifice area, with patient size defined as body surface area. A review of the Society of Thoracic Surgeons National Cardiac Database (2000-2004) yielded 48,722 patients who had isolated aortic valve replacement. This analysis is based on the cohort of 42,310 patients with the 8 most prevalent valve types with manufacturer's labeled sizes 19 mm through 29 mm. Multivariable logistic regression models were employed to determine the effects of body surface area, effective orifice area, geometric orifice area, and selected derived indices (eg, effective orifice area/body surface area) on risk-adjusted operative mortality. In separate multivariable models, effective orifice area and geometric orifice area were both inversely correlated with operative mortality. However, an unanticipated finding was that with either effective orifice area or geometric orifice area held constant, body surface area was significantly and inversely correlated with operative mortality. When patients were stratified by effective orifice area, geometric orifice area, or manufacturer's labeled valve size and type, elevations in body surface area were associated with a decrease rather than an increase in operative mortality. Prostheses with small geometric orifice area or small effective orifice area are associated with increased operative mortality after isolated aortic valve replacement. Even for valves with small effective orifice area, however, mortality decreases as body surface area increases. With respect to operative mortality, therefore, our results do not support using arbitrary cutoff values of effective orifice area/body surface area to determine the valve to utilize in a given patient.

Effects of Body Surface Area Estimates on Predicted Energy Requirements and Heat Stress

The 0.09×W0.67 equation (where W = weight in kilograms) used to estimate body surface area (SA) in cattle energy requirements models was developed using measurements of sheep that weighed between 24 and 38kg. The SA estimates it produced were compared with those of the equation 0.14×W0.57, based on Holstein cattle weighing 41 to 617kg. The estimate of SA produced by the first equation was 23% greater for a 650-kg cow than that obtained by the second equation. The impact of SA estimates on thermal comfort range and development of cold and heat stress effects was calculated, using a thermal balance model, for a 600-kg cow producing 35kg/d. Predicted metabolic heat production increment at −10°C ambient temperature with 0.5 m/s wind velocity was 0.44Mcal/d and 1.21Mcal/d by the first and second equation, respectively. Predicted lower critical temperature (LCT) was −8.7°C by the first equation and −0.6°C by the second equation, an 8°C difference. The LCT difference between SA estimates increased from 4.6 to 9.4°C, with milk production rising from 10 to 45kg/d. By the first equation, skin nonevaporative heat loss started to decrease at 15°C and became close to nil at and ambient temperature of 35°C, whereas by the second equation, respective values were 10°C and 39°C, a 5°C shift in the estimated temperature at which thermal stress would start developing. The larger SA and skin water loss predicted by the first equation reduced by 50% the respiratory heat loss involved in maintenance of thermal balance at higher temperatures for a 600-kg cow. The second equation seems preferable for Holstein SA estimation since it is based on Holstein cattle data. It provides more adequate estimates of energy requirement in the cold and of heat stress relief needs for Holstein cattle.

Pharmacokinetic and pharmacodynamic properties of docetaxel: results of phase I and phase II trials.

The pharmacokinetics of docetaxel as investigated in Phase I and Phase II trials are discussed. Phase I trials have shown that docetaxel exhibits linear pharmacokinetics consistent with a three-compartment model. Population pharmacokinetic and pharmacodynamic analysis of the results of 22 nonrandomized Phase II trials with nonlinear mixed-effects modeling showed that the interpatient variability of docetaxel pharmacokinetics is mainly related to body surface area and hepatic function. The effect of body surface area on clearance does not present a problem, since the dose of docetaxel is adjusted for body size. However, patients with impaired liver function are at increased risk of serious adverse effects (febrile neutropenia, severe infections, severe stomatitis, and toxic death) during treatment with docetaxel 100 mg/ m2. Patients with impaired liver function should receive a reduced dose (75 mg/m2). The presence of liver metastases without impaired liver function had no effect on docetaxel's clearance or safety, suggesting that a dose of 100 mg/m2 is well tolerated in such patients. Docetaxel pharmacokinetics and pharmacodynamics determined in Phase I and Phase II trials indicate a need to adjust the dosage for body surface area and liver function.

Neuromuscular Blockade with Vecuronium in Paediatric Patients with Burn Injury

1. The effect of body surface area (BSA) burn injury on neuromuscular pharmacodynamics of vecuronium was evaluated. 2. The neuromuscular responses of 15 burned children were compared with those in five controls. 3. The effective dose for 50% suppression of twitch tension (ED50) was 34 micrograms kg-1 for patients with less than 40% BSA burn, 55 micrograms kg-1 for 40-60% BSA burn, and 65 micrograms kg-1 for patients with greater than 60% BSA burn. These values were significantly higher than the value for control patients, which was 18 micrograms kg-1. 4. Burn injury induces a resistance to the neuromuscular effects of vecuronium, the magnitude of which is related to burn size.

Neuromuscular blockade with vecuronium in paediatric patients with burn injury.

1. The effect of body surface area (BSA) burn injury on neuromuscular pharmacodynamics of vecuronium was evaluated. 2. The neuromuscular responses of 15 burned children were compared with those in five controls. 3. The effective dose for 50% suppression of twitch tension (ED50) was 34 micrograms kg-1 for patients with less than 40% BSA burn, 55 micrograms kg-1 for 40-60% BSA burn, and 65 micrograms kg-1 for patients with greater than 60% BSA burn. These values were significantly higher than the value for control patients, which was 18 micrograms kg-1. 4. Burn injury induces a resistance to the neuromuscular effects of vecuronium, the magnitude of which is related to burn size.