Desired Target Range Research Articles

Oxygen saturation targeting—an illusion

The optimal oxygen saturation for very preterm infants has been extensively discussed, primarily because of the potential for competing outcomes. A lower saturation range target can decrease retinopathy of prematurity, but may increase mortality, and a higher target range can increase the severity or frequency of bronchopulmonary dysplasia. Which target range is optimal for neurodevelopment remains of conjecture. Three trials reported almost 5000 randomized infants in aggregate, and each trial was interpreted by the authors somewhat differently (NEJM 2013;368:294-104; NEJM 2010;362:1959-69; and JAMA 2013;309:2111-20). The neurodevelopmental outcomes should be available soon, which will then allow for a meta-analysis of the trials. However, a consensus of all investigators is that it is very difficult to keep the oxygen saturation in the desired target range. That difficulty is highlighted in this issue of The Journal in a report by Lim et al, who evaluated oxygen saturation targeting at 88% to 92% and with alarms set at 85% to 94% when oxygen was used for infants receiving continuous positive airway pressure. The authors found that these infants spent 31% of the time in the target range despite a major nursing effort. The infants were outside of the wider alarm limits almost 50% of the time. The neonatal community will need to use the information from the 3 large oxygen targeting trials and from reports such as this one by Lim et al to develop practical goals for oxygen targeting. Article page 730▶ Oxygen Saturation Targeting in Preterm Infants Receiving Continuous Positive Airway PressureThe Journal of PediatricsVol. 164Issue 4PreviewThe precision of oxygen saturation (SpO2) targeting in preterm infants on continuous positive airway pressure (CPAP) is incompletely characterized. We therefore evaluated SpO2 targeting in infants solely receiving CPAP, aiming to describe their SpO2 profile, to document the frequency of prolonged hyperoxia and hypoxia episodes and of fraction of inspired oxygen (FiO2) adjustments, and to explore the relationships with neonatal intensive care unit operational factors. Full-Text PDF

Interventions for erythropoietin-resistant anaemia in dialysis patients

People living with end-stage kidney disease (ESKD) often develop anaemia. Erythropoiesis-simulating agents (ESAs) are often given to people living with ESKD to maintain haemoglobin at a level to minimise need for transfusion. However, about 5% to 10% of patients with ESKD exhibit resistance to ESAs, and observational studies have shown that patients requiring high doses of ESA are at increased risk of mortality. This review aimed to study the effects of interventions for the treatment of ESA-resistant anaemia in people with ESKD. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE for randomised controlled trials (RCT) that involved participants with ESKD on dialysis or who were pre-dialysis patients with chronic kidney disease (stage 5). Date of last search: April 2013. ESA resistance was defined as failure to achieve or maintain haemoglobin/haematocrit levels within the desired target range despite appropriate ESA doses (erythropoietin ≥ 450 U/kg/wk intravenously or ≥ 300 U/kg/wk subcutaneously; darbepoetin ≥ 1.5 µg/kg/wk) in people who were not nutritionally deficient, or who had haematological or bleeding disorders. Extended inclusion criteria for ESA hyporesponsive state were: erythropoietin dose ≥ 300 U/kg/wk and ≥ 150 U/kg/wk for intravenous administration; or ≥ 200 U/kg/wk and ≥ 100 U/kg/wk for subcutaneous administration; or darbepoetin dose ≥ 1.0 µg/kg/wk). Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). Titles and abstracts of 521 records were screened, of which we reviewed 99 from the full text. Only two studies matched our inclusion criteria. One study compared intravenous vitamin C versus no study medication for six months in 42 ESKD patients on haemodialysis who required intravenous erythropoietin (dose ≥ 450 U/kg/wk). The other included study compared high-flux dialyser versus low-flux dialyser for six months in 48 haemodialysis patients who required subcutaneous erythropoietin (dose ≥ 200 U/kg/wk). Because interventions differed, data could not be combined for quantitative meta-analysis. There was inadequate evidence identified to inform recommendation of any intervention to ameliorate ESA hyporesponsiveness. Adequately powered RCTs are required to establish the safety and efficacy of interventions to improve responsiveness to ESA therapy.

Treatment of Hypothyroidism: Possibilities on the Horizon

We would like to invite you to attend the upcoming spring symposium ‘‘Treatment of Hypothyroidism: Exploring the Possibilities.’’ We hope you will share the enthusiasm of the organizing committee regarding our exciting spectrum of topics and speakers. Although thyroid hormone therapy is by no means in its infancy, many aspects of its use are prescient and remain the subject of debate. We have progressed from the use of dried thyroid glands by ancient Chinese cultures (1), to the pioneering use of thyroid extracts given subcutaneously or orally in the 1890s (2), to the routine use of desiccated porcine or bovine thyroid preparations, and their subsequent replacement by synthetic levothyroxine during the mid-1970s (3). The expectation that use of levothyroxine would provide complete resolution of the constellation of symptoms that characterize hypothyroidism was a reasonable, but nevertheless overly optimistic, hope. Revolutionary though the availability of convenient, effective, and reliable synthetic thyroid hormone preparations has been, the specter of incomplete resolution of all symptoms associated with the hypothyroid condition has not left us. Individuals with hypothyroidism and normal thyrotropin (TSH) values may have less psychological well-being (4–6) and more fatigue (7) than individuals without thyroid disease. Some (8,9), but not all (10), studies suggest that serum triiodothyronine (T3) may be lower in levothyroxine-replaced patients than in the euthyroid population. Trials of combined therapy with both thyroxine (T4) and T3 in unselected populations have generally been disappointing (11–14). The seeming irreversibility of some ramifications of hypothyroidism may potentially be explained by the existence of genetic variations in deiodinases, TSH receptors, and thyroid hormone transporters (15–17). Our understanding of how such discoveries should influence our approach to the treatment of hypothyroidism will be advanced by adequately powered, prospective trials of the response of individuals harboring these genetic variations to specific therapies. Randomized, blinded, rigorously conducted, within-individual comparisons of therapy that can be subjected to metaanalysis may also advance our understanding (18). Through such means, the options of both synthetic and natural combination therapies will continue to be investigated. The possibility that some thyroid derivatives such as thyronamines have physiologic roles may need to be considered (19). Although there has been a hiatus since such products were reported in the literature (20), preparations of T3 with a physiologic extended-release profile are also under development and may be one of our options for therapy in the future. Stem cell technology may also be applied in the future to reverse the athyreotic state (21). As we learn more about the complexities of treating this condition, we are also learning that seemingly simple aspects of therapy such as achieving acceptable adherence to prescribed therapy and maintaining a TSH value within a desired target range cannot always be accomplished (22–24). In addition, different patient groups may require different approaches. Treating hypothyroidism in the elderly (24), for example, may not require the same therapeutic goals and frequency of monitoring as treatment of other populations such as those who are pregnant (25,26). In conjunction with the work of the American Thyroid Association Task Force on Thyroid Hormone Replacement and Use of Thyroid Hormone Analogues, we have organized a spring meeting that is devoted to these topics. We hope this meeting, scheduled in Washington, DC, on April 25 and 26, will be a forum conducive to exploring new research developments affecting these issues. As a starting point, the symposium will have a half-day of basic science that will review

Individualized targeted glucose control to avoid hypoglycemia

Hyperglycemia and hypoglycemia have been linked to worse outcomes in critically ill patients. While there is controversy as to the optimal tightness of glucose control in critically ill patients, there is agreement that an upper limit to safe glucose levels exists and that avoiding hypoglycemic episodes should be prioritized. Our algorithm can assist clinicians in maintaining blood glucose ([Gbl]) within a desired target range while avoiding hypoglycemia.

Maternal Hyperphenylalaninemia: Rapid achievement of metabolic control predicts overall control throughout pregnancy

Women with hyperphenylalaninemia are at risk of having offspring affected with the maternal phenylketonuria syndrome. Here we analyze the effect of the intervention of a nutritionist on plasma phenylalanine control in Maternal Hyperphenylalaninemia. We analyzed a retrospective cohort of 35 completed pregnancies in 20 women with Maternal Hyperphenylalaninemia who visited the metabolic nutritionist during the pregnancy to achieve metabolic control. Women who promptly achieved metabolic control had lower plasma phenylalanine concentrations for the remainder of the pregnancy when compared to women who did not achieve prompt control, and this difference reached statistical significance. The achievement of plasma phenylalanine concentrations within the desired target range by the time of the second visit to the nutritionist is a strong predictor of the ability to maintain the desired target range of plasma phenylalanine for the remainder of the pregnancy. Furthermore, we demonstrate that phenylalanine tolerance increases significantly by trimester in women with classical and variant hyperphenylalaninemia.

Evaluation of a vancomycin dosing nomogram in achieving high target trough concentrations in Taiwanese patients

The use of a vancomycin dosing nomogram is an alternative and more cost-effective method to conventional dosing; it reliably allows the achievement of trough vancomycin serum concentrations of 5-15 mg/l, with a successful clinical response. Recent guidelines have further recommended that the trough concentration be maintained at 15-20mg/l for complicated infections. However, to date no published nomogram has been constructed to achieve the optimal trough of 15-20mg/l in an Asian population. This study aimed to develop two vancomycin nomograms for the achievement of trough concentrations of 5-15 mg/l and 15-20mg/l in the Taiwanese population, and to ensure the clinical efficacy and safety of such nomograms. The estimated concentrations and the real concentrations in our patient population were compared between six pharmacokinetic models to see which was the most precise. As the Ambrose method was the best at predicting the trough, this was used to create two nomograms, one for a target trough at 5-15 mg/l and the other for a target trough at 15-20mg/l. We then evaluated the nomograms by analyzing the number of patients with the target vancomycin trough concentration, clinical and microbiological outcomes, and safety. More patients who had dosing according to the nomogram had a vancomycin trough concentration within the desired target range than patients who had conventional dosing (65.1% vs. 32.1%, p = 0.001). These patients also had a higher rate of 'cure' as the clinical response (35.7% vs. 27.1%) and 'eradication' as the microbiological response (46.4% vs. 29.2%), and a lower rate of nephrotoxicity (14.3% vs. 22.9%). For the patients with a complicated infection, more had a trough between 15 and 20mg/l when vancomycin was dosed with the nomogram than when dosed conventionally (41.2% vs. 12.1%, p = 0.019). We found that when dosing vancomycin with these nomograms, patients tended to have vancomycin trough concentrations within the target range and also to have a better outcome with regard to clinical efficacy and the safety profile.

Profile of peginesatide and its potential for the treatment of anemia in adults with chronic kidney disease who are on dialysis

Peginesatide is a synthetic, dimeric peptide that is covalently linked to polyethylene glycol (PEG). The amino acid sequence of peginesatide is unrelated to that of erythropoietin (EPO) and is not immunologically cross-reactive with EPO. Peginesatide binds to and activates the human EPO receptor, stimulating the proliferation and differentiation of human red cell precursors in vitro in a manner similar to other EPO-stimulating agents (ESAs). In Phase II and III studies in dialysis and predialysis patients, peginesatide administered once monthly was as effective as epoetin alfa given thrice weekly (dialysis patients) or darbepoetin given once weekly (nondialysis patients), in correcting anemia of chronic kidney disease as well as maintaining hemoglobin within the desired target range. In the dialysis population, the reported side-effect profile of peginesatide was comparable to that known with other marketed ESAs. In the nondialysis studies, compared with those treated with darbepoetin, patients treated with peginesatide experienced a higher adverse-effect profile. Peginesatide is likely to be licensed for treatment of renal anemia in dialysis patients and not in nondialysis patients. Despite this limitation, peginesatide is likely to prove valuable in treating dialysis patients because of its infrequent mode of administration, thereby allowing for a reduced number of injections, with associated better compliance, reduced cold storage requirement, and improved stock accountability. PEGylated therapeutic proteins can elicit immunological response to the PEG moiety of the therapeutic complex. Only long-term experience and post-marketing surveillance will address whether this immunological response will have any impact on the clinical efficacy or safety of peginesatide in clinical practice.

Model-based regulation of glucose in critical care

Glucose control in critical care has been shown to improve patient outcome, yet tight glucose control has led to increased hypoglycemia in the clinic. We employed a systems engineering approach to assist clinicians in maintaining blood glucose within a desired target range while avoiding hypoglycemia in the critically ill. The long-term vision is a decision support system that provides recommended insulin and glucose administrations leading to patient-specific achievement of tight glucose control without hypoglycemia.

Different algorithms for glycemic control will yield different results

To the Editor, We read with interest Abdelmalak et al.’s recent randomized controlled trial of insulin infusion algorithms. As stated in the title, ‘‘validation’’ of the algorithm is successful as reported. However, further statistical comparisons reported between the groups (Table 2) lose significance once the significant differences between the two treatment algorithms are appreciated. The conventional group is noteworthy in that so few patients (15%) were treated with insulin compared with those treated in the intensive group (90%). While the targets of glycemic control differed between the two groups, it is unclear how the conventional group could be expected to achieve glycemic control with such infrequent use of insulin. If an appropriate comparison is to be made between the two groups, treatment initiation should be equivalent. In the target group, insulin was started at a glucose level exactly that of the upper target limit (6.1 mmoL L). However, in the conventional group, insulin was introduced at a glucose level of 11.9 mmoL L, which is 7.5% above the upper target limit (11.1 mmoL L). Given the anticipated delay to achieve target range after start of insulin, the conventional group was disadvantaged from the outset, and assigning statistical significance to the % time in the relative target range favours the intensive group (Table 2). Furthermore, the desired target range prejudices the conventional treatment group further as that of the intensive group is significantly narrower (27-37% of outer limits vs 10-11%, respectively), again favouring the intensive group since % time within target is a reported measure. In Table 2, assigned statistical significance to differences in time within a glucose range of 4.4-6.1 mmoL L or even [ 6.1 mmoL L will obviously favour the intensive group, since the conventional group never received insulin at a glucose 8.3 mmoL L. We appreciate the authors’ publication of a detailed safe and effective insulin strategy. However, although statistical differences in glucose measures were found between the two groups, we caution that these are to be expected given the inherent inequalities assigned to the non-insulin conventional group management. Future prospective evaluations could include the same initial glucose trigger followed by divergent insulin algorithms. If separate triggers are chosen, insulin must be initiated at an equivalent point within the trigger range, and ranges should be mathematically comparable.

Unfractionated Heparin Dose Requirements Targeting Intermediate Intensity Antifactor Xa Concentration During Pregnancy

To describe unfractionated heparin (UFH) dosing requirements and monitoring parameters to achieve target antifactor Xa concentrations in pregnant women receiving intermediate-dose UFH therapy. Retrospective cohort analysis. Centralized anticoagulation service in an integrated health care delivery system. Twenty-five pregnant women (who had 27 pregnancies) who received intermediate-dose UFH between January 1, 1998, and March 31, 2005. Demographic and clinical data were retrieved by using an integrated electronic medical, pharmacy, and laboratory records system. The primary outcome was the required UFH dose at the time of first target antifactor Xa level achieved. Antifactor Xa levels were measured at the mid-dosing interval for UFH. An antifactor Xa assay concentration of 0.1-0.3 unit/ml was used as the target range for intermediate-dose UFH for antithrombotic management of pregnant women as described in the American College of Chest Physicians clinical practice guidelines. The mean UFH dose required to achieve this target antifactor Xa range was 236.9 units/kg/day. The UFH doses required to achieve target antifactor Xa levels correlated significantly with patient weight (r = 0.682, p<0.001). The final UFH dose/kg required at the end of pregnancy was similar to that at the first target level (p>0.05) when adjusted for weight. However, the total daily amount of UFH did increase by the end of pregnancy (21,889 vs 19,320 units, p=0.02). There was an average of 7.9 antifactor Xa determinations and 3.1 dosage modifications during the mean of 19 weeks of antenatal UFH therapy. Most (62%) antifactor Xa levels were within the target range. No thromboembolic events, heparin-induced thrombocytopenia, or osteopenic fracture occurred. There was one hemorrhagic complication that resolved with temporary withdrawal of UFH. Pregnant women required a mean UFH dose of 236.9 units/kg/day to achieve the targeted antifactor Xa level of 0.1-0.3 unit/ml. The required UFH doses correlated with patient weight, and most antifactor Xa levels were within the desired target range. These findings may assist clinicians in more precisely initiating and monitoring intermediate-dose UFH in pregnant patients.

Prospective Evaluation of An Argatroban Dosing Nomogram Using the Ecarin Chromogenic Assay at a Tertiary Institution

There is a lack of consensus on how to best monitor therapy with the direct thrombin inhibitor argatroban. Currently, the most commonly used test is the activated partial thromboplastin time (aPTT). However, it has limited reliability, as it is easily affected by other factors, and the target is unclear in patients whose baseline values are abnormal. The ecarin chromogenic assay (ECA) reaction time is strongly correlated with plasma argatroban concentrations (r2 = 0.9994), and thus, can be used for direct quantification of argatroban concentrations. Moreover, the ECA is unaffected by low levels of prothrombin and fibrinogen, making it a more reliable and accurate test. Our institution developed a unique dosing and monitoring protocol for argatroban therapy incorporating the use of nomograms to dose argatroban and the ECA to monitor argatroban concentrations. The purpose of this study was to evaluate the ability of our current argatroban protocol to achieve and maintain ECA levels within the desired target range of 0.2 to 0.5 mcg/mL, validate the safety and efficacy of an ECA-based nomogram, and determine the relationship between argatroban concentrations and aPTT values. We conducted a prospective observational study of all patients receiving argatroban at the University Health Network (UHN) from September 1, 2007 to May 15, 2008. The UHN consists of three tertiary care hospitals in Toronto, Canada. The argatroban protocol consists of an initial infusion rate and two dose titration nomograms, one based on the ECA and the other based on the aPTT (for dose adjustment when the ECA result was unavailable during evenings and weekends). The recommended initial infusion rate was 1 mcg/kg/min, with a lower rate of 0.5 mcg/kg/min reserved for patients with liver dysfunction and/or an increased risk of bleeding. Both ECA levels and aPTT values were measured 6 hours after the initiation of argatroban and any change in rate. The primary outcome measures were the proportion of patients who achieved argatroban concentrations within the target range after the first level, the number of rate changes required to achieve target levels, and the proportion of time spent in the target range in the first 24, 48 and 72 hours. Secondary outcome measures included the proportion of patients who developed a thrombotic event or major bleed, as well as the correlation between argatroban concentrations and aPTT values. A total of 33 patients were enrolled. Protocol violations in the initial dosing and titration of argatroban led to the exclusion of 6 patients from all primary outcome analyses. Of the patients with ECA levels available at the initial rate, 35% of all patients had levels in the target range with the first ECA level. This proportion increased to 54% for patients started at 1 mcg/kg/min. The mean number of rate changes required to achieve levels in the target range was 1.15 and the mean time was 21.7 hours. The proportion of time spent in the target range in the first 72 hours was 78%. Two patients (6%) had thrombotic events during argatroban therapy with levels in the target range, and 1 patient (3%) who had previously bled prior to argatroban therapy had a confirmed major bleed. The correlation co-efficient between ECA levels and aPTT using 125 data points was 0.2475. In conclusion, our institution's argatroban protocol enabled the majority of patients to achieve target argatroban concentrations in a timely manner, and resulted in safe and effective anticoagulation. Most patients could be started at a dose of 1 mcg/kg/min. The aPTT is poorly correlated with argatroban concentrations, we recommend using the ECA to more directly quantify argatroban concentrations and to dose and monitor argatroban therapy.

Effects of Music on Physiological and Perceived Exertion Responses to Varying Exercise Modes

Music is considered a motivational stimulator during exercise and a distraction from the discomfort and fatigue caused by physical activity. Previous studies have examined these effects, especially in terms of intensity, but few have compared a variation of exercise mode. PURPOSE: To investigate the effects of music on perceived exertion (RPE) and blood pressure (BP) responses during three different modes of aerobic exercise at a prescribed moderate intensity of exercise heart rate. METHODS: Eight relatively physically active students performed a submaximal Astrand cycle ergometer (BE) test and three moderate intensity (75% of predicted HRmax), submaximal steady state exercise sessions in a randomized fashion on a treadmill, rpm independent workload BE, and elliptical trainer (ET) with and without music. Heart rate (HR) and BP were measured before, twice during, and immediately following the activity while RPE (peripheral and overall) was assessed at three times during each exercise bout. To simulate realistic exercise conditions, visual and auditory distractions were not eliminated from the environment. Statistical analysis consisting of ANOVA and t-tests were performed with significance set at the .05 level. RESULTS: HR was kept within the desired target range for each condition and exercise session (151.3 ± 6.2 with music and 149.8 ± 7.1 without, mean ± SD). Overall RPE values with music (11.6 ± 1.9, 12 ± .7, and 12.7 ± 2.1 for the treadmill, ET, and BE, respectively) were similar (not significantly different) to those without music 12.8 ± 1.9, 12.5 ± 2.2, and 12.6 ± 2.1, in the same order). Peripheral RPE scores were similarly not significantly different for the treatment conditions. Systolic BP was higher with music during BE and ET but not significantly different (means = 145.1 vs. 139.8 and 137.8 vs 133.5 mmHg, respectively). CONCLUSIONS: These results support previous research studies (Copeland and Franks, 1991) that have not found an effect of music in lowering RPE in trained individuals (Matesic and Cromartie, 2002) during exercise. It is possible that the stimulatory and distractive qualities of music together negate each other's effect on RPE, especially in typical non-sterile surroundings. Musical stimulation of BP may vary according to mode and should be further investigated.

The effect of epoetin dose on hematocrit

Nearly all dialysis patients receive epoetin therapy to treat anemia. Using the United States Renal Data System, we monitored the 14,001 patients aged 65 and older who started dialysis and epoetin treatment in 2003-2004. We estimated the dose-response relationship for the average epoetin dose and hematocrit during a 3-month initiation and subsequent 3-month maintenance phase using a marginal structural model to adjust for measured time-dependent confounding by indication. During the initiation phase, an S-shaped dose-response relationship for average weekly epoetin dose and hematocrit response was found. Average hematocrit levels rose as the epoetin dose was increased from 9,000 to approximately 22,500 units per week. At higher doses, the effect of increasing epoetin was minimal with average hematocrit levels plateauing at 38.5%, but this was less evident in the maintenance phase. Among patients who reached this phase, doses required to maintain the hematocrit level were lower than those required to achieve similar hematocrit levels in the initiation phase. The dose-response curve found in our study suggests that published recommendations for starting dose are appropriate, and a starting dose of 7,500-15,000 units per week can maintain the hematocrit level in the desired target range of 33-36%.

Multiple target detection for stepped multiple‐frequency interrupted CW radar

AbstractThis paper proposes a multiple target detection system using stepped multiple frequency ICW (Interrupted Continuous Wave) radar. The proposed system can obtain a short observation time compared to a conventional up/down sweep FMCW (Frequency‐Modulated Continuous Wave) system or a two‐frequency CW system with less computational complexity than a two‐dimensional super‐resolution system by using a new transmission frequency sequence intended for short‐range targets and a single‐dimension super‐resolution system that preprocesses a target velocity detection process through the use of an ordinary Fourier transformation. In addition, the proposed system can obtain a desired target range and velocity resolution with a transmission frequency bandwidth less than a pulse compression system or an FMCW system. The proposed system can also avoid pairing malfunctions which lead to problems with FMCW systems. Range separation of multiple equal‐velocity targets, a principal problem in two‐frequency CW systems, can also be obtained. Computer simulations show that as a radar system, the proposed system is expected to improve the above‐mentioned problems of conventional radar systems at practical input SN values. © 2007 Wiley Periodicals, Inc. Electron Comm Jpn Pt 2, 90(10): 49–59, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ecjb.20388

Utilization of a Computerized Intravenous Insulin Infusion Program to Control Blood Glucose in the Intensive Care Unit

This proof of concept study was designed to evaluate the safety and effectiveness of an intravenous insulin dosing calculator, the Clarian GlucoStabilizer program, and to determine the feasibility of its use as part of a glycemic control program. This paper discusses the impact of the GlucoStabilizer program on the glycemic control of intensive care patients with hyperglycemia. Patients admitted to the intensive care unit (ICU), requiring intravenous insulin, were treated using the GlucoStabilizer program. This program calculates an insulin drip rate based on the low and high blood glucose (BG) levels of the desired target range, the patient's current and previous BG levels, and an insulin sensitivity factor, with a goal of safely and expeditiously achieving and maintaining the patient's BG in the target range. From October 2004 through March 2006, the GlucoStabilizer program has been used to treat 2,398 patients in the ICUs, with 177,279 BG measurements in its database. In these patients, 61.0% of BGs have been in the target range of 80-110 mg/dL, while 90.9% have been in the wider range of 60-150 mg/dL. The average BG was 106.5 mg/dL (SD 39.1 mg/dL), and the frequency of hypoglycemia (BG <50 mg/dL) was 0.4%. These results compare favorably with the level of glycemic control in the 3 months before implementation of the GlucoStabilizer program. Use of the GlucoStabilizer program in the ICU resulted in improved glycemic control compared to the previous manually calculated glycemic control protocols.

Insulin Growth Factor-Based Dosing of Growth Hormone Therapy in Children: A Randomized, Controlled Study

Weight-based dosing of GH is the standard of care for short children, although IGF-I is thought to be the main mediator of GH actions on growth. The objective of the study was to test whether IGF-I levels achieved during GH therapy are determinants of the growth responses to GH treatment. This was a 2-yr, open-label, randomized, IGF-I concentration-controlled trial. Prepubertal short children [n = 172, mean age 7.53 yr, mean height sd score (HT-SDS) -2.64] with low IGF-I levels (mean IGF-I SDS -3.56) were randomized to receive one of two GH dose-titration arms in which GH dosage was titrated to achieve an IGF-I SDS at the mean [IGF((low)) group, n = 70] or the upper limit of the normal range [+2 SDS, IGF((high)) group, n = 68] or to a comparison group of conventional GH dose of 40 microg/kg/d (n = 34). The study was conducted in a multicenter, outpatient setting. Change in HT-SDS over 2 yr was measured. One hundred forty-seven patients completed the trial. Target IGF-I levels were achieved in the dose-titration arms within 6-9 months. The changes in HT-SDS were +1.0, +1.1, and +1.6 for conventional, IGF((low)), and IGF((high)), respectively, with IGF((high)) showing significantly greater linear growth response (P < 0.001, compared with the other two groups). The IGF((high)) arm required higher doses (>2.5 times) than the IGF((low)) arm, and these GH doses were highly variable (20-346 microg/kg/d). Multivariate analyses suggested that the rise in the IGF-I SDS significantly impacted height outcome along with the GH dose and the pretreatment peak-stimulated GH level. IGF-I-based GH dosing is clinically feasible and allows maintaining serum IGF-I concentrations within the desired target range. Titrating the GH dose to achieve higher IGF-I targets results in improved growth responses, although at higher average GH doses.

Warfarin: almost 60 years old and still causing problems

Warfarin: almost 60 years old and still causing problems

Initial Dosing of Paricalcitol Based on PTH Levels in Hemodialysis Patients With Secondary Hyperparathyroidism

Adjustment of the initial dose of paricalcitol in hemodialysis patients with secondary hyperparathyroidism (SHPT) on the basis of severity of SHPT generally is preferred in current practice. Whether the proposed dose, based on the formula baseline intact parathyroid hormone (iPTH [picograms per milliliter]) divided by 80, is the most appropriate has not been assessed adequately. A double-blind randomized trial comparing iPTH/80 dose with the immediately lower iPTH/120 dose was undertaken. Forty-three hemodialysis patients with iPTH levels between 300 and 900 pg/mL (300 and 900 ng/L) were followed up for 12 weeks. The primary outcome was control of iPTH levels within a target range between 150 and 300 pg/mL (150 and 300 ng/L). No difference between the 2 dose groups was noted in time to achieve target iPTH levels of 150 to 300 pg/mL (150 to 300 ng/L). More episodes of excessive decrease in iPTH levels occurred in the iPTH/80 group compared with the iPTH/120 group (P = 0.003). Nine patients in the iPTH/80 group (45%) versus 2 patients in the iPTH/120 group (10%) had iPTH levels less than 150 pg/mL (<150 ng/L) in at least half the measurements performed during the second half of the study (P = 0.034). Increases in calcium levels were greater in the iPTH/80 group at all times during the study (P < 0.05 at weeks 4 and 10). The number of required dose reductions was significantly greater in the iPTH/80 group compared with the iPTH/120 group (P = 0.008). In hemodialysis patients with SHPT, a lower initial dose of iPTH/120 shows efficacy similar to that of the already widely used iPTH/80 scheme in reaching target iPTH levels (150 to 300 pg/mL [150 to 300 ng/L]), with less required dose adjustments, lower increase in calcium levels, and lower cost. In addition, the initial dose of paricalcitol based on the iPTH/80 formula leads significantly more patients to excessive suppression of iPTH (<150 pg/mL [<150 ng/L]) than the iPTH/120 dose.

Management of hyperlipidaemia associated with heart transplantation.

The past 20 years have seen considerable advances in the field of organ transplantation that have together led to a notable increase in survival rates and a reduction in postoperative morbidity of transplant recipients. However, these advances have been accompanied by the appearance of other complications of transplantation, such as post-transplant hyperlipidaemia, hypertension and graft coronary vasculopathy (GCV). GCV is an accelerated form of atherosclerosis in transplanted hearts that has proven to be one of the most important late complications of heart transplantation and is the single most limiting factor for long-term survival. The most important factors favouring the development of hyperlipidaemia after heart transplantation are inappropriate diet in combination with reduced physical activity, adverse effects of immunosuppressive therapy (ciclosporin [cyclosporin], corticosteroids) and polygenic hypercholesterolaemia in combination with ischaemic cardiomyopathy. The treatment of hyperlipidaemia in heart transplant recipients results in a variety of complications and side effects. In particular, interactions between lipid-lowering drugs and immunosuppressive therapy have been observed. Early attempts at treatment with bile acid binding agents and nicotinic acid derivatives often proved insufficiently effective, and led to unacceptable adverse effects and significant disturbances of ciclosporin metabolism. Fibric acid derivatives provided moderate reductions in triglyceride and total cholesterol levels that were mostly--with the exception of gemfibrozil--accompanied by significant impairment of renal function. Probucol achieved only an unsatisfactory reduction in low-density lipoprotein (LDL) cholesterol. Omega-3 fatty acids lower cholesterol levels and improve endothelial function in heart transplant recipients; however, the significance of these effects is still under discussion. As in the general patient population, use of HMG-CoA reductase inhibitors (statins) achieved significant reductions in cholesterol levels. Use of these substances has resulted in significantly extended long-term survival times, significantly less GCV and fewer severe graft rejections. Selective cholesterol absorption inhibitors, administered with or without statins, could provide another treatment option for heart transplant patients with hypercholesterolaemia. In severe familial hypercholesterolaemia, which is rarely observed in heart transplant recipients, treatment with statins can be combined with extracorporeal cholesterol elimination procedures such as heparin induced extracorporeal LDL cholesterol precipitation (HELP). HELP enables total cholesterol levels to be kept within any desired target range, and has been used successfully and without adverse effects in heart transplant recipients.

Low-dose Cyclosporin A Therapy in Treating Chronic, Noninfectious Uveitis

To describe the authors' approach to the management of patients with recalcitrant, chronic, endogenous uveitis using low-dose Cyclosporin A (CSA) alone or in combination with other immunosuppressive agents with attention to the anti-inflammatory efficacy, visual outcome, and side effects of therapy. The authors reviewed the records of 50 patients (92 eyes) with uveitis of various etiologies who had been treated with low-dose CSA (2.5-5.0 mg/kg daily) alone or in combination with prednisone and/or azathioprine (1.5-2.0 mg/kg daily). The median follow-up on low-dose CSA was 16 months (range, 6-64 months). Inflammatory control was achieved in 68 (73.9%) eyes, while persistent inflammatory activity was observed in 14 (15.2%). Thirty-eight (41%) eyes improved two Snellen lines or more, 43 (47.0%) stabilized, and 11 (12.0%) lost two lines or more. The CSA was discontinued because of nephrotoxicity in three patients and in each of two with systemic hypertension and constitutional intolerance to the drug, respectively. Thirteen patients enjoy inflammatory remission with this regimen. Low-dose CSA used alone or in combination with other immunosuppressive agents is effective in achieving inflammatory control with a favorable visual outcome and provides a useful steroid-sparing strategy in the management of chronic endogenous uveitis. The CSA-associated toxicity may be reduced by initiating therapy at very low initial doses, with incremental dosage escalation to the desired target range.