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.

Delirium in the intensive care unit: are we helping the patient?

The intensive care unit (ICU) represents a dynamic interaction between patient factors and interventional factors. The complexity of this situation can generate an impaired consciousness in the patients. The critical care provider is faced with deducing the etiology and treatment of delirium in the ICU. Many of the therapeutic agents that are used in the ICU may precipitate delirium. Patients may also experience delirium as part of their underlying medical conditions. Withdrawal syndromes, delirium tremens in particular, are known to cause delirium. By a combination of appropriate selection of medications and an awareness of delirium as a side effect, the patient in the ICU may be treated in a manner to minimize the clouding of consciousness. An understanding of the proposed pathophysiology of various types of delirium will allow appropriate clinical measures to be taken.

Management of wounds and wound infections in the intensive care unit.

Many factors combine to make management of wounds and wound infections in patients in intensive care units (ICUs) a complex task. An understanding of the anatomy, pathophysiology, and bacteriology provides a framework to approach these patients. The patient's underlying disease influences the care of the wound. Wound factors such as necrotic tissue, bacterial load, or presence of fistulae or a foreign body have important impact on the patient's care. With assessment and knowledge of normal healing, timely intervention in the ICU can identify patients whose wounds are not healing properly and allow for corrective interventions to help the patient return to normal function.

Intravascular tumor: a previously unreported finding of glucagonoma.

Glucagonoma is a relatively rare pancreatic islet cell tumor. Historically, these tumors present a typical constellation of symptoms including diabetes, weight loss, anemia, necrolytic migratory erythematous rash, and propensity for thrombosis. This clinical presentation is described as the glucagonoma syndrome. The syndrome can be confirmed with the use of serum measurements of glucagon levels and immunohistochemical assay of the tumor. Variations from the classic syndrome have been described, and serum measurements of glucagon in patients with suspected islet cell tumors can identify subsets of patients with glucagonoma who do not exhibit the classic syndrome. In our case, the unusual presentation of glucagonoma included the previously unreported component of an intravascular venous extension of tumor.

Combined local hyperthermia and immunotherapy treatment of an experimental subcutaneous murine melanoma.

Immunotherapy (IT) has become an accepted therapeutic modality for a limited number of tumor types. One of the limiting factors in the use of interleukin-2 (IL-2) has been dose-related toxicity. We undertook these studies to study the effects of combined therapy on a murine melanoma. The B16 melanoma was implanted in the right hindlimb of C57BL/6 mice and therapy begun on day 3 (microscopic tumor model) or day 10 (macroscopic tumor model). Animals were divided into four groups: No therapy, local hyperthermia (HT) alone (45 degrees C x 15 minutes on days 3 and 6 or days 10 and 13), HT+IL-2 at 300,000 IU ip tid, and HT+IL-2 at 600,000 IU ip tid. We have shown in multiple previous experiments that IL-2 alone at these doses has no effect on tumor growth; these groups were omitted. In the microscopic model, tumors in the no treatment group were an average of 400 mm2. Animals treated with HT alone had a mean tumor size of 300 mm2. However, tumors in animals receiving both therapeutic modalities measured a mean of 100 mm2 (300,000 IU IL-2 ip tid) and 80 mm2 (600,000 IU IL-2 ip tid). In the macroscopic tumor model, tumors in animals receiving no treatment were an average of 7.5 times larger than on day 10, in animals receiving HT alone were an average of 5 times larger, animals receiving IL-2 were 2.95 times larger (both dose levels). These results show that combined IT+HT therapy resulted in significantly (P < .05) reduced growth with both microscopic and macroscopic tumors compared to HT alone or no therapy in a murine subcutaneous melanoma model using doses significantly lower than those usually needed to observe a therapeutic response with IL-2 used alone. This study further supports the use of this combined modality approach in patients with advanced malignancies.

Local hyperthermia abrogates the anti-immunotherapeutic effect of interleukin-8.

The therapeutic efficacy of cellular immunotherapy depends not only on the anti-tumor activity of the administered effector cells but also on their ability to gain access to the tumor by extravasation. Although interleukin-8 (IL-8) has been shown to prevent the vascular leak associated with IL-2, it also abrogates the anti-tumor effect of IL-2. We undertook these studies to determine if LHT could abrogate the anti-immunotherapeutic effect of IL-8, since IL-8 inhibits leukocyte adhesion. C57BL/6 mice were divided into four groups of six animals each after induction of MCA-105 fibrosarcoma inoculated into the right hindlimb on day 0 and were treated beginning on day 3 as follows: no therapy, IL-2 alone (1.02 x 10(6) IU ip tid on days 3-7), IL-2 + IL-8 (9.6 ng ip tid on days 3-7), and IL-2 + IL-8 + LHT (45C x 15 min on days 3, 5, and 7). Tumor growth was measured on days 10-21 and analyzed by Wilcoxon rank-sum analysis. IL-2 reduced tumor growth significantly (P < .05) compared to no therapy, and IL-8 abrogated the anti-tumor effect of IL-2, resulting in tumor growth in animals receiving IL-2 + IL-8, similar to the no therapy group (P > .05). However, addition of LHT to IL-2 + IL-8 resulted in significantly (P < .05) less tumor growth than no therapy or IL-2 + IL-8. Activity of the mice was scored as an indicator of systemic toxicity. We found that IL-8 was able to increase the activity (P = .07) of the mice when administered with IL-2. These results suggest that IL-8 may protect the tumor-bearing animal from the systemic toxicity of IL-2, while LHT abrogates the anti-immunotherapeutic effect of IL-8.

Immunotherapy and whole-body hyperthermia as combined modality treatment of a subcutaneous murine sarcoma.

Interleukin-2 and hyperthermia have been used individually to treat a variety of tumors in both experimental and human trials. Combined adoptive immunotherapy and hyperthermia is an exciting new line of investigation. Previous work in our laboratory has shown that combined local hyperthermia and rIL-2 therapy can significantly decrease the rate of tumor growth. In this study, we investigated the effect of combined whole-body hyperthermia (WBHT) and rIL-2 on the growth of subcutaneous MCA-105 murine tumors in C57BL/6 mice. Treatment of both microscopic (day 3) and macroscopic (day 10) tumors was evaluated. In the treatment of microscopic tumors, animals received either no treatment; rIL-2 (3 x 10(5) IU ip tid) on days 3-7; plus WBHT (41 degrees C for 30 min) on days 3, 5, and 7; or WBHT only days 3, 5, and 7. In treating macroscopic tumors, animals received either no treatment; rIL-2 on days 10-14; plus WBHT on days 10, 12, and 14; or WBHT only on days 10, 12, and 14. While combined treatment and WBHT alone had no significant effect on the growth of microscopic tumors, combined IL-2 and WBHT significantly reduced the rate of tumor growth of macroscopic tumors. These results suggest that the tumor microenvironment plays a critical role in combined WBHT and rIL-2 therapy, and may be due to effects of WBHT on the tumor vasculature.