rDNA insulin glargine U300 - a critical appraisal.

BACKGROUND: As the first once-daily basal insulin analog, insulin glargine 100 U/mL (Gla-100; Lantus®) rapidly evolved into the most commonly prescribed insulin therapy worldwide. However, this insulin has clinical limitations. The approval of new basal insulin analogs in 2015 has already started to alter the prescribing landscape. OBJECTIVE: To review the available evidence on the clinical efficacy and safety of a more concentrated insulin glargine (recombinant DNA origin) injection 300 U/mL (Gla-300) compared to insulin Gla-100 in patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM). METHODS: The following electronic databases were searched: PubMed and MEDLINE (using Ovid platform), Scopus, BIOSIS, and Google Scholar through June 2016. Conference proceedings of the American Diabetes Association (2015-2016) were reviewed. We also manually searched reference lists of pertinent reviews and trials. RESULTS: A total of 6 pivotal Phase III randomized controlled trials known as the EDITION series were reviewed. All of these trials (n=3,500) were head-to-head comparisons evaluating the efficacy and tolerability of Gla-300 vs Gla-100 in a diverse population with T1DM and T2DM. These trials were of 6 months duration with a 6-month safety extension phase. CONCLUSION: Gla-300 was as effective as Gla-100 for improving glycemic control over 6 months in all studies, with a lower risk of nocturnal hypoglycemia significant only in insulin-experienced patients with T2DM. Overall, patients on Gla-300 required 10%-18% more basal insulin, but with less weight gain compared with Gla-100.

Dyshormonia Iatrogenica: crossroads of medicine, malpractice law, and professional ethics in clinical endocrinology.

OBJECTIVE: To present 2 challenging cases of patients who request endocrine therapies that their physician considers to be outside of the standard of care. METHODS: With these complex cases as a backdrop, we explore the constructs of medicine, malpractice law, and professional ethics that guide physicians' medical decision-making processes. RESULTS: These cases illustrate a common conundrum for clinical endocrinologists, who often find themselves struggling to balance patient satisfaction and well-being with generally accepted standards of medical care. From the perspective of a malpractice lawyer, we review the keys to limiting medicolegal liability, with emphasis on thorough documentation, informed consent, and effective doctor-patient communication. We then review the constructs of professional ethics that guide patient care, with emphasis on virtues of the "good physician," patients' right to self-determination, and paternalism. Finally, we explore some justifications for a compassionate physician to refuse a patient's desired treatment plan. CONCLUSION: In the end, we hope that this manuscript helps to facilitate best medical, legal, professional, and ethical practices of clinical endocrinology.

Adapting to the new consensus guidelines for managing hyperglycemia during critical illness: the updated Yale insulin infusion protocol.

OBJECTIVE: To report our preliminary experience with the revised, more conservative Yale insulin infusion protocol (IIP) that targets blood glucose concentrations of 120 to 160 mg/dL. METHODS: We prospectively tracked clinical responses to the new IIP in our medical intensive care unit (ICU) by recording data on the first 115 consecutive insulin infusions that were initiated. All blood glucose values; insulin doses; nutritional support including intravenous dextrose infusions; caloric values for enteral and parenteral nutrition; and use of vasopressors, corticosteroids, and hemodialysis or continuous venovenous hemodialysis were collected from the hospital record. RESULTS: The IIP was used 115 times in 90 patients (mean age, 62 [±14 years]; 51% male; 35% ethnic minorities; 66.1% with history of diabetes). The mean admission Acute Physiology and Chronic Health Evaluation II score was 24.4 (±7.5). The median duration of insulin infusion was 59 hours. The mean baseline blood glucose concentration was 306.1 (±89.8) mg/dL, with the blood glucose target achieved after a median of 7 hours. Once the target was reached, the mean IIP blood glucose concentration was 155.9 (±22.9) mg/dL (median, 150 mg/dL). The median insulin infusion rate required to reach and maintain the target range was 3.5 units/h. Hypoglycemia was rare, with 0.3% of blood glucose values recorded being less than 70 mg/dL and only 0.02% being less than 40 mg/dL. In all cases, hypoglycemia was rapidly corrected using intravenous dextrose with no evident untoward outcomes. CONCLUSIONS: The updated Yale IIP provides effective and safe targeted blood glucose control in critically ill patients, in compliance with recent national guidelines. It can be easily implemented by hospitals now using the original Yale IIP.

Comprehensive management of post-transplant diabetes mellitus: from intensive care to home care.

Post-transplant diabetes mellitus (PTDM) is a common complication of solid organ and hematopoietic transplantation. This clinically oriented review article briefly summarizes the pathophysiology of PTDM, then presents a comprehensive clinical approach to diagnosis and therapy. Topics include the key clinical aspects of PTDM screening, diagnosis, and management during all phases following transplantation from the intensive care unit, to the inpatient ward, to the outpatient arena.

Unusual case of amiodarone-induced thyrotoxicosis: "illicit" use of a technetium scan to diagnose a transiently toxic thyroid nodule.

OBJECTIVE: To present an unusual case of amiodarone-induced thyrotoxicosis (AIT) associated with an autonomously functioning thyroid nodule, which was detected by means of a technetium scan; review the existing literature regarding the association of AIT with autonomous thyroid nodules; and explore the use of radioisotope imaging studies in patients with AIT. METHODS: We describe a 62-year-old man with paroxysmal atrial fibrillation, receiving long-term amiodarone therapy, who was referred by his cardiologist for evaluation of abnormal thyroid function tests. He was found to have an unusual case of AIT, associated with an autonomously functioning thyroid nodule. RESULTS: Thyroid function studies obtained by the patient's cardiologist had shown a completely suppressed thyrotropin level and a free thyroxine level of 3.5 ng/dL. A 24-hour thyroid iodine 123 uptake and technetium Tc 99m pertechnetate scan revealed a "single, strong focus in the right thyroid lobe, with the rest of the thyroid gland...not well visualized." Thyroid ultrasonography disclosed a single, well-defined 1.5-cm solid nodule. Repeated thyroid function studies revealed a normal thyrotropin level of 2.87 micro IU/mL and a normal free thyroxine level of 2.4 ng/dL. The patient was managed conservatively with follow-up surveillance. CONCLUSION: Prospective studies should be performed to better ascertain the value of Tc 99m thyroid scanning in determining the cause of AIT. Until such studies have been completed, we suggest that nuclear studies are unlikely to be cost-effective for assessing all patients with AIT. One logical strategy would be to gain experience with scans in only those patients with known thyroid nodules, which have been detected during physical examination or by ultrasonography. The potential clinical utility of such an approach would be of considerable interest.

Hypoglycemia reduces the blood-oxygenation level dependent signal in primary auditory and visual cortex: a functional magnetic resonance imaging study.

Studies of the effects of hypoglycemia on the brain using neurocognitive testing have suggested that mainly complex functions subserved by secondary and tertiary cortex are affected by mild to moderate hypoglycemia and that intensively treated patients with Type I diabetes mellitus (T1DM) may have altered sensitivity to the central nervous system effects of hypoglycemia. Functional magnetic resonance imaging provides a sensitive, regionally-specific probe of possible neurophysiologic changes related to hypoglycemia in the brain. Eleven intensively-treated T1DM patients and 11 matched non-diabetic controls took part in a 2-day protocol in which functional magnetic resonance imaging (MRI) was used to measure changes in the patterns of brain activation produced by simple auditory and visual stimuli in different conditions. On one day, participants were euglycemic the entire time. On the other day, an initial 50-min euglycemic period was followed by a 50-min hypoglycemic period. Results indicated that hypoglycemia reduced the amplitude of the blood-oxygenation level dependent response in primary auditory and visual cortex to simple auditory and visual stimuli. The latency and duration of the transient hemodynamic response function were not affected. Responses to hypoglycemia were similar in diabetic and non-diabetic participants. These results suggest that mild to moderate hypoglycemia may alter the balance of blood flow and oxygen extraction when glucose levels are lowered. Intensively-treated T1DM, with its attendant frequent hypoglycemic episodes, did not seem to alter hypoglycemic responses in primary visual and auditory cortex.

"Glucometrics"--assessing the quality of inpatient glucose management.

BACKGROUND: For patients with diabetes, the quality of outpatient glycemic control is readily assessed by hemoglobin A1c. In contrast, standardized measures for assessing the quality of blood glucose (BG) management in hospitalized patients are lacking. Because of recent studies demonstrating the benefits of strict glycemic control in critically ill patients, hospitals nationwide are dedicating resources to address this important issue. To facilitate advances in this nascent field, standardized metrics for inpatient glycemic control should be developed and validated. METHODS: We used 1 month of fingerstick BG levels from a general hospital ward to develop and test three analytic models, based on three units of inpatient BG analysis: population (i.e., ward), patient-day, and patient. To assess the effect of the source of blood samples, we repeated these analyses after adding venous plasma glucose levels. Finally, we employed an idealized intensive care unit data set to establish "gold standard" metrics for inpatient glycemic control. RESULTS: Mean and median BG levels and the proportion of BG levels within an "optimal" range (80-139 mg/dL) were similar among the three models, whereas hypoglycemic and hyperglycemic event rates varied considerably. Inclusion of venous glucose levels did not substantially affect the results. Of the three models tested, the patient-day model appears to most faithfully reflect the quality of inpatient glycemic control. Achieving 85% of BG levels within optimal range may be considered gold standard. CONCLUSIONS: If validated elsewhere, these "glucometrics" would permit objective comparisons of inpatient glycemic control among hospitals and patient care units, and would allow institutions to gauge the success of their quality improvement initiatives.

"Waste not, want not": determining the optimal priming volume for intravenous insulin infusions.

BACKGROUND: Insulin adsorbs to plastics used for intravenous (IV) tubing. As a result, clinical IV insulin infusion procotols advise an initial priming volume of up to 50 mL, which may be wasteful-especially since most institutions use 100-mL IV solution bags. In this brief report, we sought to determine the optimal priming volume required for clinical IV insulin infusions. METHODS: One hundred units of regular human insulin was dissolved into 100 mL of 0.9% NaCl. Employing a standard polypropylene infusion set, a priming infusion was started. At 10- mL intervals, from 0 to 50 mL, effluent was collected directly into glass vials. After dilution (1:10,000) using a proprietary buffer, insulin concentrations were then measured using a double antibody radioimmunoassay. Twenty individually prepared insulin bags were tested in this manner. RESULTS: Insulin levels without prime were 15.8% [95% confidence interval (CI), 9.1-22.6%] lower than insulin levels following 50 mL of prime (designated as "maximal values"). After a priming volume of 10 mL, insulin adsorption losses fell to a marginally significant 6.6% (95% CI, 0.1-13.1%). Following 20 mL of prime, insulin concentrations were indistinguishable from maximal values (3.4% loss, 95% CI, -0.2% to 7.1%). CONCLUSIONS: For standard IV insulin infusions, a priming volume of 20 mL is sufficient to minimize the effect of insulin adsorption losses to IV lines. Priming volumes exceeding 20 mL are wasteful, increase costs, and generate unnecessary work for nurses and pharmacists.

Memoirs of a root canal salesman: the successful implementation of a hospital-wide intravenous insulin infusion protocol.

OBJECTIVE: To summarize key metabolic results from use of the Yale Insulin Infusion Protocols (IIPs), as well as the primary barriers to their implementation. To offer practical suggestions for overcoming these barriers, drawing from our experiences "selling root canals" during the successful implementation of our hospital-wide IIPs. METHODS: Since 2002, Yale IIPs have been employed to achieve strict glycemic control in our ICU patients. Barriers to protocol implementation were noted, and strategies were designed to overcome these barriers. RESULTS: In 2002, we implemented Version 1 of the Yale IIP, which purposefully targeted conservative blood glucose (BG) levels of 100 to 139 mg/dL. Following extensive hospital-wide experience with Version 1, Version 2 of the IIP (which debuted in 2004) successfully lowered BG targets to 90 to 119 mg/dL, with minimal impact on observed rates of hypoglycemia. These nurse-driven protocols safely and effectively controlled glucose levels in our ICU patients, without the need for ongoing physician supervision. CONCLUSION: This work describes the successful implementation of an evolving hospital-wide IIP. To be successful, an IIP must account for the following essential elements: (1) the current BG level, (2) the velocity of glycemic change, and (3) the current insulin infusion rate. We have reviewed five "points of emphasis" to consider when implementing an IIP.

Effects of hypoglycemia on human brain activation measured with fMRI.

Functional magnetic resonance imaging (fMRI) was used to measure the effects of acute hypoglycemia caused by passive sensory stimulation on brain activation. Visual stimulation was used to generate blood-oxygen-level-dependent (BOLD) contrast, which was monitored during hyperinsulinemic hypoglycemic and euglycemic clamp studies. Hypoglycemia (50 +/- 1 mg glucose/dl) decreased the fMRI signal relative to euglycemia in 10 healthy human subjects: the fractional signal change was reduced by 28 +/- 12% (P < .05). These changes were reversed when euglycemia was restored. These data provide a basis of comparison for studies that quantify hypoglycemia-related changes in fMRI activity during cognitive tasks based on visual stimuli and demonstrate that variations in blood glucose levels may modulate BOLD signals in the healthy brain.

Antecedent hypercortisolemia is not primarily responsible for generating hypoglycemia-associated autonomic failure.

Hypoglycemia-associated autonomic failure (HAAF) occurs commonly in patients with longstanding diabetes, placing affected patients at increased risk for severe hypoglycemia. Previous studies have suggested that hypoglycemia-induced hypercortisolemia may be responsible for blunting subsequent sympathoadrenal responses to hypoglycemia; however, this view remains highly controversial. In this work, we sought to better define the role of antecedent hypercortisolemia in generating HAAF, using two complimentary experimental models in nondiabetic human subjects: 1) antecedent hydrocortisone infusions (simulating physiologic cortisol responses to hypoglycemia) and 2) antecedent hypoglycemia, with and without concurrent blockade of endogenous cortisol production using oral metyrapone. Our results showed no effect of antecedent hypercortisolemia on epinephrine responses to subsequent hypoglycemia (area under the curve/time 280 +/- 53 vs. 337 +/- 57 pg/ml, P = 0.16). Of particular importance, selective blockade of endogenous cortisol production during antecedent hypoglycemia had no effect on subsequent counterregulatory responses to hypoglycemia. Compared with epinephrine responses following antecedent euglycemia (area under the curve/time 312 +/- 38 pg/ml), epinephrine responses were comparably blunted following antecedent hypoglycemia, regardless of whether concurrent metyrapone blockade was employed (198 +/- 28 vs. 192 +/- 28 pg/ml, P = NS). Similar results were obtained for glucagon and ACTH levels. Considered together, these observations provide strong evidence that hypoglycemia-induced hypercortisolemia is not primarily responsible for the generation of HAAF.

Hemorrhagic pheochromocytoma associated with systemic corticosteroid therapy and presenting as myocardial infarction with severe hypertension.

Pheochromocytomas classically present with paroxysms of hypertension and adrenergic symptoms including headaches, palpitations, tremor, and anxiety. However, these tumors can be clinically silent and occasionally present only when catecholamine release is up-regulated by exogenous stimuli. In addition, the clinical presentation of pheochromocytoma can mimic a number of more common medical conditions, including migraine headaches, cardiac arrhythmias, and myocardial infarction, making diagnosis difficult. In this report, we present the case of a young woman who, while receiving oral corticosteroid therapy for presumed migraine headaches, suffered a myocardial infarction and ultimately hemorrhaged into a previously undiagnosed pheochromocytoma. Our patient exhibited severe, labile hypertension after the administration of iv beta-blockade for presumed myocardial ischemia, raising our initial clinical suspicion for pheochromocytoma. In this paper we review some of the key clinical issues related to this complex case, including steroid-induced stimulation of catecholamine synthesis and release, the role of pheochromocytoma in myocardial ischemia and electrocardiographic changes, and the rare complication of tumor hemorrhage. We then briefly review the essential diagnostic and management strategies for this rare but potentially lethal tumor, with specific emphasis on pheochromocytoma-related cardiovascular emergencies and the surgical management of tumor hemorrhage.

Experience with the continuous glucose monitoring system in a medical intensive care unit.

Strict glycemic control improves clinical outcomes in critically ill patients. However, practical tools for frequent monitoring of blood glucose (BG) levels in the intensive care unit (ICU) are limited. The Continuous Glucose Monitoring System (CGMS, Medtronic MiniMed, Northridge, CA) is currently approved for detecting glycemic excursions in outpatients with diabetes mellitus. The use of this device has never been carefully examined in the inpatient setting. This preliminary study was designed to investigate the accuracy of the CGMS in critically ill patients admitted to a medical ICU (MICU). Subjects at risk for hyperglycemia were recruited from among all patients admitted to our MICU. CGMS sensors were implanted for up to 72 h. Study subjects wore between one and five consecutive sensors. Four or more standard capillary BG readings were recorded per 24 h. All paired meter-sensor (M-S) readings were used both for CGMS calibration and for data analysis. Twenty-two MICU patients wore 41 CGMS sensors, yielding 546 M-S BG pairs. Overall, the Pearson correlation coefficient ( r ) was 0.88, with a mean M-S difference of 3.3 +/- 26.7 mg/dL (0.6 +/- 17.4%) and a mean absolute M-S difference of 19.7 +/- 18.3 mg/dL (12.8 +/- 11.9%). Clarke Error Grid analysis categorized 98.7% of the M-S pairs within "clinically acceptable" zones A and B. The CGMS is promising for potential use in critically ill patients. If validated in larger studies, the device could serve as a useful research tool for investigating the role of hyperglycemia (and strict glycemic control) in ICU patients. If further developed as a "real-time" glucose sensor, CGMS technology could ultimately prove clinically useful in the ICU, by decreasing nursing workload and/or by providing alarm signals for impending glycemic excursions.

Implementation of a safe and effective insulin infusion protocol in a medical intensive care unit.

OBJECTIVE: In a recent randomized controlled trial, lowering blood glucose levels to 80-110 mg/dl improved clinical outcomes in critically ill patients. In that study, the insulin infusion protocol (IIP) used to normalize blood glucose levels provided valuable guidelines for adjusting insulin therapy. In our hands, however, ongoing expert supervision was required to effectively manage the insulin infusions. This work describes our early experience with a safe, effective, nurse-implemented IIP that provides detailed insulin dosing instructions and requires minimal physician input. RESEARCH DESIGN AND METHODS: We collected data from 52 medical intensive care unit (MICU) patients who were placed on the IIP. Blood glucose levels were the primary outcome measurement. Relevant clinical variables and insulin requirements were also recorded. MICU nurses were surveyed regarding their experience with the IIP. RESULTS: To date, our IIP has been employed 69 times in 52 patients admitted to an MICU. Using the IIP, the median time to reach target blood glucose levels (100-139 mg/dl) was 9 h. Once blood glucose levels fell below 140 mg/dl, 52% of 5,808 subsequent hourly blood glucose values fell within our narrow target range; 66% within a "clinically desirable" range of 80-139 mg/dl; and 93% within a "clinically acceptable" range of 80-199 mg/dl. Only 20 (0.3%) blood glucose values were <60 mg/dl, none of which resulted in clinically significant adverse events. In general, the IIP was readily accepted by our MICU nursing staff, most of whom rated the protocol as both clinically effective and easy to use. CONCLUSIONS: Our nurse-implemented IIP is safe and effective in improving glycemic control in critically ill patients.

Improving glycemic control in the cardiothoracic intensive care unit: clinical experience in two hospital settings.

OBJECTIVE: Recent studies suggest that strict perioperative glycemic control improves clinical outcomes after cardiothoracic surgery. However, optimal methods and targets for controlling blood glucose (BG) levels in this setting have not been established. Currently published intensive insulin infusion protocols (IIPs) have important practical limitations, which may affect their utility. In this article, the authors present their experience with a safe, effective, nurse-driven IIP, which was implemented simultaneously in 2 cardiothoracic intensive care units (CTICUs). DESIGN: Prospective cohort study. SETTING: Tertiary referral hospital and community teaching hospital. PARTICIPANTS: CTICU patients. INTERVENTIONS: A standardized, intensive IIP was used for all patients admitted to both CTICUs. Hourly BG levels, relevant baseline variables, and clinical interventions were collected prospectively from the active hospital chart and CTICU nursing records. MEASUREMENTS AND MAIN RESULTS: The IIP was used 137 times in 118 patients. The median time required to reach target BG levels (100-139 mg/dL) was 5 hours. Once BG levels decreased below 140 mg/dL, 58% of 2,242 subsequent hourly BG values fell within the narrow target range, 73% within a "clinically desirable" range of 80 to 139 mg/dL, and 94% within a "clinically acceptable" range of 80 to 199 mg/dL. Only 5 (0.2%) BG values were less than 60 mg/dL, with no associated adverse clinical events. CONCLUSIONS: The IIP safely and effectively improved glycemic control in 2 CTICUs, with minimal hypoglycemia. Based on prior studies showing the benefits of strict glycemic control, the implementation of this IIP should help to reduce morbidity and mortality in CTICU patients.

Critical issues in endocrinology.

Endocrine emergencies are commonly encountered in the ICU. This article focuses on several important endocrine emergencies, including diabetic hyperglycemic states, adrenal insufficiency, myxedema coma, thyroid storm, and pituitary apoplexy. Other endocrine issues that are related to intensive care, such as intensive insulin therapy, relative adrenal insufficiency, and thyroid function test abnormalities are also covered in detail.