Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients

Objective: To evaluate the literature and identify important aspects of insulin therapy that facilitate safe and effective infusion therapy for a defined glycemic end point. Methods: Where available, the literature was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology to assess the impact of insulin infusions on outcome for general intensive care unit patients and those in specific subsets of neurologic injury, traumatic injury, and cardiovascular surgery. Elements that contribute to safe and effective insulin infusion therapy were determined through literature review and expert opinion. The majority of the literature supporting the use of insulin infusion therapy for critically ill patients lacks adequate strength to support more than weak recommendations, termed suggestions, such that the difference between desirable and undesirable effect of a given intervention is not always clear. Recommendations: The article is focused on a suggested glycemic control end point such that a blood glucose ≥150 mg/dL triggers interventions to maintain blood glucose below that level and absolutely <180 mg/dL. There is a slight reduction in mortality with this treatment end point for general intensive care unit patients and reductions in morbidity for perioperative patients, postoperative cardiac surgery patients, post-traumatic injury patients, and neurologic injury patients. We suggest that the insulin regimen and monitoring system be designed to avoid and detect hypoglycemia (blood glucose ≤70 mg/dL) and to minimize glycemic variability. Important processes of care for insulin therapy include use of a reliable insulin infusion protocol, frequent blood glucose monitoring, and avoidance of finger-stick glucose testing through the use of arterial or venous glucose samples. The essential components of an insulin infusion system include use of a validated insulin titration program, availability of appropriate staffing resources, accurate monitoring technology, and standardized approaches to infusion preparation, provision of consistent carbohydrate calories and nutritional support, and dextrose replacement for hypoglycemia prevention and treatment. Quality improvement of glycemic management programs should include analysis of hypoglycemia rates, run charts of glucose values <150 and 180 mg/dL. The literature is inadequate to support recommendations regarding glycemic control in pediatric patients. Conclusions: While the benefits of tight glycemic control have not been definitive, there are patients who will receive insulin infusion therapy, and the suggestions in this article provide the structure for safe and effective use of this therapy.

Postmenopausal virilization, simple ovarian cyst, and hilus cell hyperplasia--is there an association?

OBJECTIVE: To report a case of virilizing ovarian hilus cell hyperplasia detected postmenopausally in association with a simple cyst and to review the related literature, including four similar cases. METHODS: Hormonal and pathologic studies were conducted, and ovarian venous catheterization was performed during total abdominal hysterectomy. RESULTS: In our 69-year-old female patient, serum testosterone levels were 508, >3,200, and 11 ng/dL, respectively, in peripheral blood preoperatively, in ovarian venous blood obtained intraoperatively, and in peripheral blood postoperatively. The wall of the cyst contained several clusters of hilus cells, which were also found asymmetrically lateralized to the affected ovary. CONCLUSION: Hilus cell hyperplasia should be suspected in any case of postmenopausal virilization in which ultrasonography or magnetic resonance imaging suggests the presence of a simple ovarian cyst.

Collective actions by physicians that do not endanger patients.

Exploitation of resident physicians still occurs and can result in working conditions so unfavorable that patients are endangered. Because residents are vulnerable to exploitation, and because they are not fully accountable for patient care or for fully developed professionalism until they have completed their training, for just ends it is morally acceptable for residents to strike. Given that the ultimate responsibility for every patient rests not with the residents but with the attending and staff physicians, in the event of a resident strike the attending and staff physician supervisors should cover patient care, at least with respect to essential services. It is not morally acceptable for attending or staff physicians who are employees to strike. Attending and staff physicians should make every effort to resolve concerns about patient care without the use of confrontation. However, it may be necessary to consider collective actions to secure certain professional interests, including an interest in patient care. For such ends, patient endangerment is an unacceptable means and contrary to the professional virtue of altruism. The strategy for a just collective action is to identify the things that physicians normally do for their employer and collectively to withhold all of them, with the single exception of patient care.

Expectations and outcomes in organ transplantation.

Research is needed on the frequency of bad outcomes in transplantation. Allocation policies and professional or institutional self-interest may affect the incidence of bad outcomes, and the need for reform is stressed. Transplant recipients who have had a bad outcome often continue to receive aggressive care. The humanistic care of patients having bad outcomes requires attention to advance directives, discussion with patient and family of alternatives to aggressive treatment, and provision of an option for home hospice care. Finally, it must be reemphasized that the average typical good outcome is extraordinarily good, restoring function of a vital organ, extending and improving quality of life, and sometimes restoring near-normal health. In no way should the fact of bad outcomes reduce our commitment to producing good outcomes.

Managing diabetes during glucocorticoid therapy. How to avoid metabolic emergencies.

Although glucocorticoid therapy carries a risk of promoting or exacerbating hyperglycemia, there are currently no established medical guidelines for detecting or managing diabetes in patients starting such therapy. The authors use three case reports to illustrate a relatively simple strategy that can be used to manage preexisting and new-onset diabetes in the primary care setting.

Silent corticotroph adenoma: case report and literature review.

OBJECTIVE: To review the initial clinical manifestations and diagnosis of silent corticotroph adenoma. METHODS: We report a case and summarize the relevant literature. RESULTS: A 52-year-old patient with hypopituitarism underwent resection of a silent corticotroph adenoma. A circulating species was detected postoperatively, reactive in a highly sensitive adrenocorticotropic hormone (ACTH) 1-39 immunoradiometric assay (IRMA) and beta-endorphin or beta-lipotropin radioimmunoassay. The basal morning cortisol concentration consistently was <10 microg/dL. Dynamic testing was performed to screen for Addison's disease, congenital adrenal hyperplasia, and Cushing's syndrome. During dexamethasone suppression, the molar concentration of circulating ACTH precursors by a two-site IRMA was 55-fold greater than the concentration of ACTH 1-39 by IRMA. We concluded that the tumor displayed impaired processing of pro-opiomelanocortin (POMC) and secreted a bioinactive POMC-derived peptide that was reactive in the ACTH 1-39 IRMA. CONCLUSION: Patients with silent corticotroph adenoma do not have clinically evident Cushing's syndrome. In some cases, bioinactive ACTH precursors may be detected by a sensitive ACTH 1-39 IRMA.

Diabetes management during glucocorticoid therapy for nonendocrine disease.

OBJECTIVE: To determine current attitudes about management of diabetes during glucocorticoid therapy for nonendocrine disease, as assessed by a pilot survey. METHODS: A 27-item questionnaire was designed to determine areas of consensus and of disagreement on diabetes management during glucocorticoid therapy for nonendocrine disease and was mailed to 84 Chicago-area academic general internists, endocrinologists, pulmonologists or allergists, rheumatologists, and certified diabetes nurse-educators. RESULTS: The response rate was 55%. For new-onset "steroid diabetes," 43% of respondents agreed with use of insulin and 44% with use of sulfonylurea therapy. Respondents indicated 91 to 95% agreement on the desirability of self-monitoring of blood glucose on initiation of glucocorticoid therapy. For a fasting plasma venous glucose level of 150 mg/dL at the time of initiation of long-term glucocorticoid therapy, 54% of respondents disagreed with immediate increase of insulin in the case of a patient already taking insulin, and 80% disagreed with immediate substitution of insulin in the case of a patient on maximal glyburide therapy (P = 0.0053 for mean change of position). During tapering of glucocorticoid therapy, 75% of respondents approved close observation without immediate insulin reduction. Two anticipatory management plans, opposed by 54% and 45% of respondents, respectively, elicited strongly correlated attitudes: immediate increase of NPH insulin dosage during initiation of glucocorticoid therapy and immediate reduction of NPH insulin dose during tapering of glucocorticoids (r = 0.6296; P<0.0001). Finally, 78% perceived a paucity of objective information about diabetes management during glucocorticoid therapy for nonendocrine disease. CONCLUSION: The surveyed sample of practitioners reported a paucity of objective data about management of diabetes during glucocorticoid therapy for nonendocrine disease and conservatism in adjusting diabetes management during initiation and tapering of glucocorticoid therapy.

Reduced expression of hexokinase II in insulin-resistant diabetes.

The regulation of hexokinase II (HKII) was examined in fat and skeletal muscle of an animal model of non-insulin-dependent diabetes mellitus, the KKAY mouse. These tissues require insulin for facilitated transport of glucose and express the insulin-responsive transporter GLUT4. The combined data from two experiments (n = 12 for each experimental condition) demonstrated mean concentrations of plasma insulin in pmol/l and glucose in mmol/l of 122 and 7.2 (control nondiabetic C57 mouse) vs. 1,118 and 29.6 (diabetic mouse), respectively. The tissues of diabetic mice compared with control mice demonstrated a reduction of HKII mRNA abundance of 68% in epididymal fat (P = 0.0001) and 34% in the quadriceps muscles (P < 0.001), with concordant reduction in the abundance of GLUT4 mRNA of 60% in epididymal fat (P < 0.001). In comparison with the results in untreated diabetic mice, diabetic animals treated with the insulin-sensitizing drug pioglitazone demonstrated an increase in the abundance of HKII mRNA with a concordant increase of GLUT4 mRNA in epididymal fat (P = 0.03 and < 0.01, respectively), and an increase of HKII mRNA in the quadriceps muscles (P < 0.05). Separate experiments demonstrated a reduction of HKII protein abundance by 61% in epididymal fat (P < 0.001, n = 12 for each experimental condition) and by 71% in the quadriceps muscles (P < 0.001, n = 6 for each experimental condition). In comparison with untreated diabetic mice, there was an increase in the abundance of HKII protein in epididymal fat of animals treated with pioglitazone (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Altered gene expression for tumor necrosis factor-alpha and its receptors during drug and dietary modulation of insulin resistance.

As obesity is a major risk factor for noninsulin-dependent diabetes mellitus, adipose tissue may generate a mediator that influences the activity of insulin on various target tissues. Recent evidence suggests that a cytokine, tumor necrosis factor-alpha (TNF alpha), may serve this role. This study investigates whether the expression of TNF alpha and its receptors is modulated during drug treatment to reduce insulin resistance. The effects of moderate weight loss by dietary restriction were also examined. We show here that a marked induction of TNF alpha mRNA occurs in adipose tissues from a mouse model of obesity-linked diabetes (KKAy) compared to that in nondiabetic mice (C57). Likewise, RNA transcripts encoding TNF R2 receptors (p75) were significantly increased in fat tissues of the obese diabetic animals. In muscle from these diabetic animals, RNA transcripts encoding both TNF R1 (p55) and R2 were significantly elevated, although R2 transcript abundance was less elevated than in fat. We also observed that the overexpression of mRNA for TNF alpha and both of its receptors could be at least partly normalized by treatment of the diabetic animals with the insulin-sensitizing agent pioglitazone. Treating of the obese diabetic animals by food restriction reduced the expression of mRNA for TNF R2 in muscle, but not fat. These results clearly indicate that gene expression for the TNF systems can be regulated by an insulin-sensitizing drug and reduction of body weight. Such findings support a role for this cytokine in the insulin-resistant diabetic state and show its modulation by therapies that reverse the disorder.

The courtship of the paying patient.

This article argues for a prohibition on the courtship of the paying patient by individual practitioners, groups, institutions, and corporations. Our society fails to provide universal access to health care. While we await societal resolution, the private provider retains partial responsibility for addressing issues of distributive justice. All private physicians, groups, institutions, and corporations should offer a fair share of underreimbursed, nonemergency care. If economic survival or beneficent economic commitments of a provider are at risk, the provider may explicitly limit underreimbursed services by a rational system of accepting or rejecting nonemergency, indigent patients. The system should be one that, if implemented by all providers, would meet regional societal needs. One might analyze the issue of courtship of the paying patient as a problem of distributive justice. The desire of paying patients to receive personalized care or nonmedical amenities and to have the freedom to buy the best possible medical care, and the economic interests of the providers (the desire of the already affluent provider to seek further gain and growth, the need of a threatened provider to survive, and the dependency of educational institutions on patient payments) all conflict with distributive justice. The marketing interest of providers conflicts with the greater need of the poor to receive information about health, and it conflicts with public need for protection against misleading solicitation. The possibly higher per capita cost of treating the poor, along with possibly lower success rates, create a conflict between cost-effective allocation of limited resources, on the one hand, and egalitarian distributive justice, on the other. The competitive market principle may even protect, rather than defeat, the principle of justice. The author, however, writing from the point of view of the physician, has analyzed the question in terms of a conflict between the economic interest of the physician (perhaps as agent of his group, institution, or corporation) and the trustworthiness of the profession. The courtship of the paying patient represents a failure of the professional virtues of truthfulness, loyalty, and respect for persons.

Acquired partial corticosterone methyl oxidase type II defect in diabetes mellitus. Case of hyperreninemic hypoaldosteronism.

The aim of this study was to investigate the pathogenesis of hypoaldosteronism in diabetes. Endogenous elevation of plasma renin activity and exogenous corticotropin were used to study steroidogenesis. Observations were made over 12 yr on the evolution and treatment of hyperkalemia in a diabetic subject. In 1977, potassium, baseline cortisol, aldosterone, and renin activity were normal; renin activity increased normally with posture; and cortisol responded normally to ACTH infusion. Nine yr later, persistent hyperkalemia was documented. Upright renin activity was elevated to 5.26 ng.L-1.s-1, with concomitant elevation of 18-hydroxycorticosterone (18-OHB) and a low-normal aldosterone level. One hour after administration of 0.25 mg i.m. cosyntropin, cortisol increased normally, aldosterone increased from 220 to 360 pM, and 18-OHB increased from 3700 to 4800 pM. During treatment with fludrocortisone, fludrocortisone with furosemide, and furosemide alone, improvement of hyperkalemia was noted. Endogenous hyperreninemia and basal elevations of 18-OHB, accompanied by limited aldosterone responsiveness to renin and ACTH, suggest the presence of a partial corticosterone methyl oxidase type II defect. Evolution of hyperkalemia between 1977 and 1986 suggests this defect was acquired.

Decreased dehydroepiandrosterone sulfate in pigmented nodular adrenal dysplasia.

Previous reports on patients with endogenous Cushing's syndrome describe low concentrations of the adrenal androgen dehydroepiandrosterone sulfate (DHEA-S) in adrenal adenoma and in a case of feminizing macronodular hyperplasia. Here we present hormonal data from two adult sisters with Cushing's syndrome as a result of pigmented nodular adrenal dysplasia. Corticotropin concentrations were in the mid-normal range, cortisol production was unaffected by administration of dexamethasone (8 mg/24 h), and baseline concentrations of DHEA-S were less than 0.5 mumol/L. A low concentration of DHEA-S in these and other previously reported patients with Cushing's syndrome correctly predicts the results of dynamic testing. Decreased DHEA-S in a patient with endogenous Cushing's syndrome can be ascertained by assay of a single sample and should prompt consideration of the diagnosis of autonomous bilateral nodular disease as well as adrenal adenoma.

Plasmapheresis: an adjunct to medical management of severe hyperthyroidism.

A woman with hyperthyroidism and myasthenia gravis developed respiratory failure in association with radiation-induced thyroiditis. Treatment with steroids, propylthiouracil, propranolol, iodine, and plasmapheresis was associated with dramatic reduction in serum triiodothyronine (T3), serum thyroxine (T4), and thyroglobulin levels and prompt recovery of the patient. The medications that this patient received have been shown to cause an abrupt decline in serum T3 levels with little or no effect on the serum T4 concentration. The 56% decline in serum T4 observed in this patient during the first 24 hours of therapy suggests that plasmapheresis may be a useful adjunct to medical therapy in selected patients with severe hyperthyroidism.

Fine needle aspiration biopsy of thyroid nodules.

The clinical value of the fine needle aspiration of thyroid nodules was evaluated by comparing preoperative cytology to subsequent pathology in 109 patients undergoing thyroidectomy. Preoperative cytology was reported as insufficient cellular material (31 patients), benign goiter (27 patients), follicular neoplasm (22 patients), thyroiditis (12 patients), suspicious for papillary carcinoma (nine patients), Hurthle cell neoplasm (five patients), medullary carcinoma (one patient), lymphoma (one patient), and metastatic adenocarcinoma (one patient). Operative findings demonstrated that the overall sensitivity of fine needle aspiration in diagnosing thyroid neoplasia (carcinoma or adenoma) was 88% and its specificity was 80%. Operation verified the cytologic diagnosis of medullary carcinoma, lymphoma, metastatic adenocarcinoma, and seven of nine papillary carcinomas. Of the five patients with an aspiration biopsy diagnosis of Hurthle cell neoplasm, three patients had carcinoma and one had an adenoma. Four carcinomas and 12 follicular adenomas were found in patients with a cytologic diagnosis of follicular neoplasm. Thyroiditis was confirmed at operation in all 12 patients with this diagnosis on fine needle aspiration. One carcinoma was found in the 27 patients with benign goiter diagnosed on cytology. Fine needle aspiration is a valuable tool that can lead to earlier diagnosis and treatment of thyroid cancer. However, a negative aspiration does not supplant good clinical judgement in determining the need for thyroidectomy.