Antifungal Dosing Considerations in Patients Undergoing Continuous Renal Replacement Therapy

Purpose of Review

The incidence of systemic fungal infections is increasing among patients admitted to the intensive care unit (ICU). Acute kidney injury (AKI) occurs in one third of ICU patients and approximately 5% require renal replacement therapy (RRT). Among those requiring RRT, continuous RRT (CRRT) is used in more than 70% of cases. This review aims to summarize antifungal dosing management in ICU patients receiving CRRT.

Recent Findings

For most antifungal agents, including new azoles such as posaconazole and isavuconazole, CRRT does not significantly affect antifungal pharmacokinetics (PK) mainly due to drug liver elimination and high protein binding. For fluconazole, increased dose is recommended during CRRT taking into account the type of CRRT mode (CVVHF or CVVHDF), membrane surface, and effluent and dialysis flow rates. A dose increase for itraconazole seems also necessary during CRRT; a dose decrease for flucytosine is probably necessary but data are too scarce to give a strong recommendation.

Summary

In ICU patients receiving CRRT, no dosing adjustment is required for the majority of antifungal agents commonly used to treat invasive fungal infections (IFIs) excepted for fluconazole, itraconazole, and flucytosine. Due to high PK variability, therapeutic drug monitoring should be considered in ICU patients receiving CRRT.

     

Expert Roundtable on Continuous Glucose Monitoring

ObjectiveThe objective of this study was to define an expert opinion on continuous glucose monitoring (CGM) in persons with type 2 diabetes mellitus, including its advantages, barriers, and best clinical practices for initiation, patient-clinician communication, and data management.MethodsA series of virtual discussions was held to recommend improvements to clinical practice and design clinical tools for primary care clinicians. Participants included endocrinologists, primary care physicians, physician assistants, advanced practice nurses, and diabetes care and education specialists.ResultsThe expert panels recommended CGM as a supplement to blood glucose monitoring and hemoglobin A1c for managing diabetes in persons with diabetes (PWDs). CGM can help predict potential pitfalls in glycemic management, including hypo and hyperglycemic excursions, which directly influence lifestyle changes, medication initiation, and dosing decisions. A toolkit was designed with practical guidance on the integration of CGM into clinical practice, interpretation of results, clinical guidelines, a patient action plan, and other useful management tools.ConclusionThis review summarizes the findings from a roundtable discussion with endocrinology and primary care clinicians, a discussion of the advantages and challenges of CGM, and clinical approaches to improving the care of PWDs. CGM offers more detailed tracking of glucose levels than blood glucose monitoring or hemoglobin A1c, and it can detect asymptomatic hypoglycemia. Specialized education of providers, the cost to patients and providers, and data management are barriers to the widespread adoption of CGM for PWDs.     

Trough Concentrations of Vancomycin in Patients Undergoing Extracorporeal Membrane Oxygenation

To investigate the appropriateness of the current vancomycin dosing strategy in adult patients with extracorporeal membrane oxygenation (ECMO), between March 2013 and November 2013, patients who were treated with vancomycin while on ECMO were enrolled. Control group consisted of 60 patients on vancomycin without ECMO, stayed in medical intensive care unit during the same study period and with the same exclusion criteria. Early trough levels were obtained within the fourth dosing, and maintenance levels were measured at steady state. A total of 20 patients were included in the analysis in ECMO group. Sixteen patients received an initial intravenous dose of 1.0 g vancomycin followed by 1.0 g every 12 hours. The non-steady state trough level of vancomycin after starting administration was subtherapeutic in 19 patients (95.00%) in ECMO group as compared with 40 patients (66.67%) in the control group (p = 0.013). Vancomycin clearance was 1.27±0.51 mL/min/kg, vancomycin clearance/creatinine clearance ratio was 0.90 ± 0.37, and elimination rate constant was 0.12 ± 0.04 h^-1. Vancomycin dosingfrequency and total daily dose were significantly increased after clinical pharmacokinetic services of the pharmacist based on calculated pharmacokinetic parameters (from 2.10 ± 0.72 to 2.90 ± 0.97times/day, p = 0.002 and from 32.54 ± 8.43 to 42.24 ± 14.62mg/kg, p = 0.014) in ECMO group in contrast with those (from 2.11 ± 0.69 to 2.37 ± 0.86 times/day, p = 0.071 and from 33.91 ± 11.85 to 31.61 ± 17.50 mg/kg, p = 0.350) in the control group.Although the elimination rate for vancomycin was similar with population parameter of non ECMO patients, the current dosing strategy of our institution for vancomycinin our ICU was not sufficient to achieve the target trough in the initial period in most patients receiving ECMO.     

Iron Metabolism in Patients Undergoing Regular Dialysis Therapy

Thirteen patients with chronic renal failure maintained on regular renal dialysis were studied. Seven proved to have iron deficiency on the basis of marrow iron studies, reticulocyte iron uptake, and saturation of the serum iron-binding capacity. They absorbed iron when given it by mouth and were able to utilize it for haemoglobin formation. Iron-deficient patients given 600 mg of ferrous sulphate daily for three months showed an increase in haemoglobin, but the failure to replace stores of iron is probably related to their relatively limited ability to absorb iron and the variable but sometimes considerable blood loss occurring with each dialysis.The loss may be occult, and prolonged iron therapy may be required. This is most safely achieved by giving iron by mouth.     

Accuracy of Continuous Glucose Monitoring Measurements in Normo-Glycemic Individuals

BackgroundThe validity of continuous glucose monitoring (CGM) is well established in diabetic patients. CGM is also increasingly used for research purposes in normo-glycemic individuals, but the CGM validity in such individuals is unknown. We studied the accuracy of CGM measurements in normo-glycemic individuals by comparing CGM-derived versus venous blood-derived glucose levels and measures of glycemia and glycemic variability.MethodsIn 34 healthy participants (mean age 65.7 years), glucose was simultaneously measured every 10 minutes, via both an Enlite^® CGM sensor, and in venous blood sampled over a 24-hour period. Validity of CGM-derived individual glucose measurements, calculated measures of glycemia over daytime (09:00h-23:00h) and nighttime (23:00h-09:00h), and calculated measures of glycemic variability (e.g. 24h standard deviation [SD]) were assessed by Pearson correlation coefficients, mean absolute relative difference (MARD) and paired t-tests.ResultsThe median correlation coefficient between CGM and venous glucose measurements per participant was 0.68 (interquartile range: 0.40–0.78), and the MARD was 17.6% (SD = 17%). Compared with venous sampling, the calculated measure of glycemia during daytime was 0.22 mmol/L higher when derived from CGM, but no difference was observed during nighttime. Most measures of glycemic variability were lower with CGM than with venous blood sampling (e.g., 24h SD: 1.07 with CGM and 1.26 with venous blood; p-value = 0.004).ConclusionIn normo-glycemic individuals, CGM-derived glucose measurements had good agreement with venous glucose levels. However, the measure of glycemia was higher during the day and most measures of glycemic variability were lower when derived from CGM.     

A Double-Needle Gold-Silver Electrodes Continuous Glucose Monitoring Device

ObjectivesDiabetes is a serious, long-term disease and the use of continuous glucose monitoring sensors can reduce reliance on other painful invasive blood testing methods such as the finger blood glucose test. According to our work, a low-cost continuous glucose sensor has been developed based on electrochemical measurement techniques.MaterialsThe sensor is based on a two needles system; a gold and a silver electrode are integrated into a circular shaped electronic printed circuit board (PCB). The sensing part is based on biological electrochemical measurements. Glucose oxidase (Gox) was used as the active sensing element and ferrocene (Fc) as a mediator. Simple and low-cost coating methods were used; these methods are self-assembled monolayers and deep coating. This will reduce the final cost of the sensor as no expensive technique was used. The electrical subsystem contains a low-noise and low-power trans-impedance front-end as well as a single-chip low-power Bluetooth microcontroller with a 12-bit Analog-to-Digital Converter (ADC).ResultsThe sensor was tested in various concentrations of glucose. As a result of initial in vitro experiments, detailed analytical performance metrics are presented. The device has consistently shown a sensitivity of 3.059 mV/(mg/dl) reading with a linear range of 0-400 mg/dl.ConclusionThe proposed study shows promising results for glucose detection. Thus, this type of sensor can be used for different analyzes targeting biological applications after further investigations and analysis.     

How Patients With Type 1 Diabetes Translate Continuous Glucose Monitoring Data into Diabetes Management Decisions

Objective: To understand how patients use continuous glucose monitoring (CGM) data in their diabetes management.Methods: We surveyed patients who regularly used CGM (>6 days per week), using 70 questions, many scenario-based. The survey had 6 sections: patient characteristics, general CGM use, hypoglycemia prevention and management, hyperglycemia prevention and management, insulin dosing adjustments (both for incidental hyperglycemia not at meals and at mealtimes), and real-time use versus retrospective analysis.Results: The survey was completed by 222 patients with type 1 diabetes. In response to a glucose of 220 mg/dL, the average correction dose adjustment based on rate of change arrows varied dramatically. Specifically, when the CGM device showed 2 arrows up (glucose increasing >3 mg/dL/minute), respondents stated they would increase their correction bolus, on average, by 140% (range, 0 to 600%). Conversely, 2 arrows down (glucose decreasing >3 mg/dL/minute) caused respondents to reduce their dose by 42%, with 24% omitting their dose entirely. Furthermore, 59% of respondents stated they would delay a meal in response to rapidly rising glucose, whereas 60% would wait until after a meal to bolus in response to falling glucose levels. With a glucose value of 120 mg/dL and a falling glucose trend, 70% of respondents would prophylactically consume carbohydrates to avoid hypoglycemia.Conclusion: CGM users utilize CGM data to alter multiple aspects of their diabetes care, including insulin dose timing, dose adjustments, and in hypoglycemia prevention. The insulin adjustments are much larger than common recommendations. Additional studies are needed to determine appropriate insulin adjustments based on glucose trend data.Abbreviations: A_1c = hemoglobin A_1c CGM = continuous glucose monitoring ROC = rate of change SMBG = self-monitored blood glucose     

Insulin Pump Therapy in Patients with Diabetes Undergoing Surgery

ObjectiveTo assess perioperative management of patients with diabetes mellitus who were being treated with insulin pump therapy.MethodsWe reviewed records for documentation of insulin pump status and glucose monitoring during preoperative, intraoperative, and postanesthesia care unit (PACU) phases of surgery.ResultsThirty-five patients (21 men) with insulin pumps underwent surgical procedures between January 1, 2006, and December 31, 2010. Mean age was 56 years, mean diabetes duration was 31 years, and mean duration of insulin pump therapy was 7 years. All patients were white, and 29 had type 1 diabetes mellitus. Of the 50 surgical procedures performed during the study period, 16 were orthopedic, 9 were general surgical, 7 were urologic, and 7 were kidney transplant operations; the remaining 11 procedures were in other surgical specialties. The mean (± standard deviation) time in the preoperative area was 118 ± 75 minutes, mean intraoperative time was 177 ± 102 minutes, and mean PACU time was 170 ± 78 minutes. Of the 50 procedures, status of pump use was documented in 32 cases in the preoperative area, 14 cases intraoperatively, and 30 cases in the PACU. Glucose values were recorded in 47 cases preoperatively, 30 cases intraoperatively, and 48 cases in the PACU.ConclusionsResults showed inconsistent documentation of pump use and glucose monitoring throughout the perioperative period, even for patients with prolonged anesthesia and recovery times. It was often unclear whether the pump was in place and operational during the intraoperative period. Guidelines should be developed for management of insulin pump–treated patients who are to undergo surgery. (Endocr Pract. 2012;18:49-55)     

Magnesium Therapy for Intractable Ventricular Tachyarrhythmias in Normomagnesemic Patients

Intractable ventricular tachyarrhythmia associated with hypomagnesemia responds well to magnesium given intravenously. Two patients with recurrent ventricular tachycardia and ventricular fibrillation associated with normal serum magnesium levels and resistant to treatment with potassium chloride, lidocaine and bretylium tosylate responded dramatically to the administration of magnesium sulfate. A third patient in whom the serum magnesium level was unknown also showed dramatic response to magnesium therapy.Magnesium depletion probably interferes with sodium-potassium adenosine triphosphatase enzyme activity and causes ionic imbalance and electrical instability of purkinje''s fibers. Without obvious magnesium depletion this element in high concentration may still prolong transient inward current, prolong the effective refractory period, increase the membrane potential and control ventricular tachyarrhythmia.When ventricular fibrillation or malignant ventricular tachycardia cannot be controlled with lidocaine and other conventional drugs, we recommend infusing magnesium sulfate, 2 to 3 grams in one minute, followed by 10 grams over five hours.     

Continuous Glucose Monitoring for Patients with COVID-19 Pneumonia: Initial Experience at a Tertiary Care Center

ObjectivePatients hospitalized with COVID-19 and hyperglycemia require frequent glucose monitoring, usually performed with glucometers. Continuous glucose monitors (CGMs) are common in the outpatient setting but not yet approved for hospital use. We evaluated CGM accuracy, safety for insulin dosing, and CGM clinical reliability in 20 adult patients hospitalized with COVID-19 and hyperglycemia.MethodsStudy patients were fitted with a remotely monitored CGM. CGM values were evaluated against glucometer readings. The CGM sensor calibration was performed if necessary. CGM values were used to dose insulin, without glucometer confirmation.ResultsCGM accuracy against glucometer, expressed as mean absolute relative difference (MARD), was calculated using 812 paired glucometer-CGM values. The aggregate MARD was 10.4%. For time in range and grades 1 and 2 hyperglycemia, MARD was 11.4%, 9.4%, and 9.1%, respectively, with a small variation between medical floors and intensive care units. There was no MARD correlation with mean arterial blood pressure levels, oxygen saturation, daily hemoglobin levels, and glomerular filtration rates. CGM clinical reliability was high, with 99.7% of the CGM values falling within the “safe” zones of Clarke error grid. After CGM placement, the frequency of glucometer measurements decreased from 5 to 3 and then 2 per day, reducing nurse presence in patient rooms and limiting viral exposure.ConclusionWith twice daily, on-demand calibration, the inpatient CGM use was safe for insulin dosing, decreasing the frequency of glucometer fingersticks. For glucose levels >70 mg/dL, CGMs showed adequate accuracy, without interference from vital and laboratory values.     

Potassium Balance and Acid-Base Changes in Patients Undergoing Regular Haemodialysis Therapy

Serial measurements of total body potassium in 21 patients with chronic renal failure being treated with three 10-hour periods of dialysis per week, against a dialysate fluid containing 1·5 mEq of potassium per litre, showed no evidence of potassium depletion. Mild hyperkalaemia was found in some patients before dialysis, correlated with the pre-dialysis hydrogen ion concentration. Hypokalaemia occurred during dialysis in almost half of the studies made; the plasma potassium concentration, however, rose to normal levels within two to four hours of stopping dialysis. A delay in the movement of potassium from the cells into the extracellular fluid is suggested as a cause for the observed hypokalaemia.In all but one patient the pre-dialysis blood pH was normal, but rose to alkalaemic levels during dialysis. A pronounced degree of hypocapnia was noted before dialysis, and this was not altered by a rising blood pH during dialysis. It is suggested that a stimulus to respiration other than the hydrogen ion gradient between the brain cells and cerebral spinal fluid may produce the observed hypocapnia.     

接受肠外营养液的非重症住院患者的血糖调控

接受肠外营养液的非重症住院患者常因手术或其他原因无法进食而采用胰岛素控制血糖,加之一些影响血糖的治疗因素存在,致使该类患者的血糖控制更加复杂。从影响血糖的因素、血糖的监测和调控方式及血糖波动的评价指标等方面论述非重症住院患者血糖的调控,着重介绍胰岛素静脉控制血糖的使用方法和基本算法,以期为临床治疗提供参考     

Continuous Monitoring of Extracellular Glucose Concentrations in the Striatum of Freely Moving Rats with an Implanted Glucose Biosensor

Abstract: We have used a glucose oxidase-based sensor implanted in the striatum of freely moving rats to determine the concentration of extracellular glucose in two distinct ways. With a modification of the zero net flux method, in which different concentrations of glucose are infused through a dialysis probe glued to the biosensor, we calculated the concentration at which there was no change in glucose current by regression analysis; this gave a concentration of 0.351 ± 0.016 m M . Calculating the concentration from the basal current and the in vitro calibration of the biosensor was not significantly different from this. The basal extracellular glucose concentration determined by either method remained constant over a period of several days. Infusion of 50 µ M veratridine through the adjacent dialysis probe caused a steep decrease in glucose current as soon as the drug reached the brain in contrast to the delayed fall (7.5 min) seen with microdialysis in previous experiments from this laboratory. These results demonstrate that this biosensor provides a direct, real-time measure of the extracellular concentration of glucose.     

Self Blood Glucose Monitoring Underestimates Hyperglycemia And Hypoglycemia As Compared To Continuous Glucose Monitoring In Type 1 And Type 2 Diabetes

Objective: When glucose records from self blood glucose monitoring (SBGM) do not reflect estimated average glucose from glycosylated hemoglobin (HgBA1) or when patients' clinical symptoms are not explained by their SBGM records, clinical management of diabetes becomes a challenge. Our objective was to determine the magnitude of differences in glucose values reported by SBGM versus those documented by continuous glucose monitoring (CGM).Methods: The CGM was conducted by a clinical diabetes educator (CDE)/registered nurse by the clinic protocol, using the Medtronic iPRO2™ system. Patients continued SBGM and managed their diabetes without any change. Data from 4 full days were obtained, and relevant clinical information was recorded. De-identified data sets were provided to the investigators.Results: Data from 61 patients, 27 with type 1 diabetes (T1DM) and 34 with T2DM were analyzed. The lowest, highest, and average glucose recorded by SBGM were compared to the corresponding values from CGM. The lowest glucose values reported by SBGM were approximately 25 mg/dL higher in both T1DM (P = .0232) and T2DM (P = .0003). The highest glucose values by SBGM were approximately 30 mg/dL lower in T1DM (P = .0005) and 55 mg/dL lower in T2DM (P<.0001). HgBA1c correlated with the highest and average glucose by SBGM and CGM. The lowest glucose values were seen most frequently during sleep and before breakfast; the highest were seen during the evening and postprandially.Conclusion: SBGM accurately estimates the average glucose but underestimates glucose excursions. CGM uncovers glucose patterns that common SBGM patterns cannot.Abbreviations: CDE = certified diabetes educator; CGM = continuous glucose monitoring; HgBA1c = glycosylated hemoglobin; MAD = mean absolute difference; SBGM = self blood glucose monitoring; T1DM = type 1 diabetes; T2DM = type 2 diabetes     

A Simple Intervention Raised Resident-Physician Willingness to Assist Transgender Patients Seeking Hormone Therapy

Objective: Lack of physician knowledge about transgender medicine is a barrier to care. An intervention with medical students changed attitudes about providing transgender medical care, but it is unknown whether at the level of postgraduate education an intervention could have a similar effect. We conducted such an intervention with resident-physicians.Methods: An intervention on transgender medicine covering the durability of gender identity and hormonal treatment regimens was added to the curriculum for residents. An anonymous survey assessed the residents' knowledge and willingness to assist with hormonal therapy before and after the lecture.Results: The percent of residents who agreed that they felt sufficiently knowledgeable to assist with hormonal therapy for a female-to-male patient increased significantly, from 5% before to 76% following the lecture (χ², 24.7; degrees of freedom, 1; P<.001). The percent of residents who reported that they felt sufficiently knowledgeable to assist with hormonal therapy for a male-to-female patient increased significantly, from 5% before to 71% following the lecture (χ², 24.0; degrees of freedom, 1; P<.001). The intervention increased resident knowledge about hormonal therapy for hypogonadal men (χ², 11.4; degrees of freedom, 1; P<.001) and women (χ², 9.4; degrees of freedom, 1; P = .002). The intervention made more residents agree that gender identity has a biologic basis that remains constant (P<.001) and that hormonal and surgical therapies should be offered (P = .047).Conclusion: The lecture significantly increased residents' knowledge and willingness to assist with hormonal therapy for transgender patients.Abbreviation: PGY = postgraduate year     

Diurnal Glucose Patterns of Exenatide Once Weekly: A 1-Year Study Using Continuous Glucose Monitoring with Ambulatory Glucose Profile Analysis

ObjectiveTo use continuous glucose monitoring (CGM) to characterize diurnal glucose patterns produced by a novel formulation of exenatide consisting of biodegradable polymeric microspheres that entrap exenatide and provide extended release enabling once-weekly administration.MethodsWe performed a subgroup analysis of patients with type 2 diabetes who participated in a multicenter trial (DURATION-1: Effects of Exenatide Long- Acting Release on Glucose Control and Safety in Subjects With Type 2 Diabetes Mellitus) comparing once-weekly with twice-daily formulations of exenatide. We are the only center to use CGM with ambulatory glucose profile (AGP) analysis to characterize glucose exposure, variability, and stability in participants assigned to exenatide once weekly.ResultsSeven of the 303 patients in the larger study population were included in the subgroup analysis. Mean age (57.6 ± 7 years), weight (102 ± 17 kg), body mass index (34 ± 3 kg/m²), and duration of diabetes (5 ± 2 years) were comparable to characteristics of the larger study population. At 30 weeks and 52 weeks, participants treated with exenatide once weekly had a mean reduction in hemoglobin A_1c level of 1.3 ± 0.3% and 1.0 ± 0.3%, respectively (P < .05). CGM analysis revealed a significant (P < .01) decrease in diurnal glucose exposure for 4 participants during nocturnal and daytime periods. Excess glucose exposure (compared with reference values) decreased in 6 of 7 participants, as did glucose variability. Glucose stability improved in 5 participants. The percentage of glucose values less than 70 mg/dL initially increased during the first half of the study then decreased to baseline levels by study end.ConclusionsIndividual glucose profiles revealed that changes in hemoglobin A_1c did not consistently parallel alterations in glucose exposure, variability, and stability. AGPs provided a visual representation of improved glucose responses to exenatide once weekly. (Endocr Pract. 2009;15:326-334)