Parenteral Nutrition The Sweet and Sour Truth. From: Division of Endocrinology, Diabetes and Bone Disease Icahn School of Medicine at Mount Sinai

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1 ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. DOI: /EP14101.ED 2014 AACE. Editorial Article EP14101.ED Parenteral Nutrition The Sweet and Sour Truth Elise M. Brett, MD, FACE, CNSC, ECNU; Jeffrey I. Mechanick, MD. FACE, FACP, FACN, ECNU. From: Division of Endocrinology, Diabetes and Bone Disease Icahn School of Medicine at Mount Sinai Correspondence address: Jeffrey I. Mechanick, MD, FACE, FACP, FACN, ECNU. Division of Endocrinology, Diabetes and Bone Disease Icahn School of Medicine at Mount Sinai 1192 Park Avenue; New York, NY DOI: /EP14101.ED 2014 AACE.

2 To the Editor: We read with great interest the papers by Olveira et al. (1) and Farrokhi et al. (2) and congratulate Endocrine Practice for inclusion of these high quality papers on the subject of parenteral nutrition therapy in the endocrinology literature. The overarching context here is that hyperglycemia and malnutrition are common and serious problems in hospital settings that often occur together and impart significant and negative clinical outcomes. Detrimental consequences of hyperglycemia among hospitalized patients have been consistently demonstrated, though specific glycemic goals have been debated. Parenteral nutrition (PN) exacerbates hyperglycemia risk due to direct infusion of dextrose into the bloodstream. This circumvents incretin effects and mechanisms that suppress hepatic gluconeogenesis and glucose uptake typically observed with enteral nutrition. (3) This may also be compounded by under-insulinization by PN prescribers, inhibition of glucose uptake with parenterally administered lipid, total calorie overfeeding with overestimated lean body weights, and immune-neuroendocrine axis activation by inflammatory cytokines, associated with insulinresistance, glucotoxicity, and beta-cell dysfunction. In fact, a systematic review of four retrospective studies examining hyperglycemia in a mixed population of critically ill and noncritically ill patients receiving PN showed a consistent finding of increased mortality if the blood glucose level was greater than 180 mg/dl. (4) Malnutrition is common and associated with poor outcome in critically ill patients. (5) In patients deemed at high nutritional risk and unable to tolerate adequate enteral nitrogen and/or energy, relatively early PN therapy is appropriate (italicized words highlight our knowledge gaps in this burgeoning field where strong, conclusive evidence is lacking). According to the landmark studies by Van den Berghe (6,7), in which the majority of post surgical patients received PN during the first week, tight glycemic control with intensive (intravenous) insulin therapy was associated with favorable clinical outcomes. (6) (7) However, the glycemic targets (BG

3 mg/dl) in these results have been challenged voraciously and the interaction between adequate nutrition and parameters of glycemic control have plagued consistent and pragmatic interpretations. The article by Olverira et al. (1) reports the prevalence of hyperglycemia in patients receiving PN across 19 hospitals in Spain. As expected, this figure was high: 56.6% of patients had a known disorder of carbohydrate metabolism prior to initiating PN therapy, and 71.6% required at least some insulin during their course of therapy. This study highlights the need for nutrition support practitioners to anticipate, prevent, and aggressively manage hyperglycemia in all at-risk patients, and not simply react to high glucose readings. The authors identify several risk factors for predicting hyperglycemia in patients to receive PN therapy including hemoglobin A1c. When possible, assessment of hemoglobin A1c prior to initiation of therapy is particularly useful, but initiation of nutrition support should not be delayed pending the hemoglobin A1c result. These days, many hospitals have nurse-driven intravenous insulin protocols to manage critically ill patients with hyperglycemia. The current study included only non-critically ill patients and it would be impractical to routinely treat these patients with separate, dedicated intravenous insulin drips. The Endocrine Society Guidelines from 2012 very generally state that regular insulin administered as part of the PN formulation can be both safe and effective with recommendations for additional subcutaneous and separate intravenous insulin as needed.(8) However, there are currently no standardized protocols for the use of insulin in the PN formula, so patients are managed according to individual provider or institutional usual practice habits often without the involvement of an endocrinologist. In this study, only 35.8% of patients received insulin in the PN formulation, including only 61 and 68% of patients with diabetes (known and unknown), and only 2/3 of patients with diabetes actually achieved desired glucose targets. In our experience, non-icu patients with diabetes, pre-diabetes, and stress hyperglycemia are easily managed with nutritive insulin (insulin to cover the dextrose) added to the PN bag and subcutaneous rapid-acting insulin correction doses every 6 hours. Basal insulin can be provided subcutaneously or also added to the PN. Essentially all patients with a prior history of diabetes require at least some insulin in the PN and this can be anticipated and initiated 3

4 with the start of PN therapy, rather than waiting for the inevitable uncontrolled hyperglycemia. We were pleased to note that patients in this study did not seem to be overfed total calories, demonstrating a necessary departure from the ills of the past practice. A strategy of preemptively restricting dextrose infusions to below goal at the start of PN therapy can facilitate glycemic control; insulin and dextrose can then be commensurately up-titrated to meet metabolic needs. The non-icu patient receiving only PN for nutrition represents a unique opportunity to achieve glucose control with low glycemic variability. This metabolic clamping results as carbohydrate infusion is consistent throughout the day, without relying on varying oral intakes or enteral absorption factors, and insulin delivery is similarly controlled and not dependent on timing of insulin injections or consistency of subcutaneous insulin action and absorption. As compared to the ICU patient, fewer stressors and pharmaceuticals are playing a role so glucose levels can be smoother. In the study by Farookhi et al., a retrospective chart review of 276 medical and surgical ICU patients treated with PN was conducted. Glycemic variability was found to be a significant independent predictor of mortality among patients with diabetes at all levels of glycemic control (2), consistent with the findings of Krinsley several years earlier (9). Hence, with well-designed protocols to control glucose using insulin in the PN, mortality should not be increased in non-icu patients as a results of PN per se. In short, research must be conducted to confirm the optimal insulin delivery method for the heterogeneous group of hyperglycemic patients who require PN therapy. Protocols should then be developed for the initiation and ongoing management of these patients as their illnesses progress. Moreover, guidelines for glycemic goals should be developed specifically for the non- ICU patient receiving PN. The AACE/ADA Consensus Statement on Inpatient Glycemic Control recommends a pre-meal target of <140 mg/dl for most non-critically ill patients in conjunction with random blood glucose values <180 mg/dl (10). According to the document Insulin therapy is highly recommended, with glucose targets as defined previously on the basis of the severity of illness. (9) However, glycemic targets remain undefined for the non-icu patient who is receiving continuous nutrients via PN. It is not known whether a random blood glucose target of 180 mg/dl 4

5 is an appropriate acceptable upper limit when nutrients are constantly being infused: there is no fasting state, ambient glucose levels remain fairly consistent, and sudden hypoglycemia is less likely to occur. Indeed, the role of PN among hospitalized patients has been historically confusing and frustrating. PN is an admixture of many nutrients, each having complex interacting roles as therapeutic agents. Insulin is one of the few drugs that are compatible for direct addition to the PN admixture, and its administration in this manner has distinct advantages. It is with properly conducted research that the sweet and sour truth of this specialized intervention can be far more palatable. References. 1) Olveira G, Tapia MJ, Ocón J, et al. Prevalence of diabetes, prediabetes and stress hyperglycemia, insulin therapy and metabolic control in patients on total parenteral nutrition (prospective multicenter study). Endocr Pract in press. 2) Farrokhi F, Chandra P, Smiley D, et al. Glucose Variability is an Independent Predictor of Mortality in Hospitalized Patients Treated with Total Parenteral Nutrition. Endocr Pract 2014;20: ) Guan J, Zucker PF, Behme MT, et al. Insulin resistance prevented by portal delivery of insulin in rats with renal subcapsular islet grafts. Diabetes Mar;46: ) Kumar PR, Crotty P, Raman M, Hyperglycemia in Hospitalized Patients Receiving Parental Nutrition Is Associated with Increased Morbidity and Mortality: A Review, Gastroenterology Research and Practice, vol. 2011, 7 pages, ) Giner M, Laviano A, Meguid MM, Gleason JR. In 1995 a correlation between malnutrition and poor outcome in critically ill patients still exists. Nutrition. 1996;12:

6 6) Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med Nov 8;345: ) Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Crit Care Med. 2003;31: ) Umpierrez GE, Hellman R, Korytkowski MT, et al. Endocrine Society. Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. J Clin Endocrinol Metab Jan;97: ) Krinsley JS. Glycemic variability: A strong independent predictor of mortality in critically ill patients. Crit Care Med 2008;: ) Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care Jun;32: