June 2016 E-Journal Club

Greetings,

We do not host a traineeship session in June since we start taking turns recharging our clinical batteries during assorted staycations and vacations. We have also been hard at work putting the finishing touches on our newest edition of our Traineeship manual.

Our journal club article for June dealt with the effect of diabetes-specific EN formula in adult ICU patients.

June Citation:

Mesejo A, Montejo-González JC, Vaquerizo-Alonso C et al. Diabetes-specific enteral nutrition formula in hyperglycemic, mechanically ventilated, critically ill patients: a prospective, open-label, blind-randomized, multicenter study. Crit Care. 2015 Nov 9;19:390.

Summary:

This was a multicenter, randomized, unblinded study (with concealed allocation) comparing a new diabetes-specific EN formula, a commercial diabetes-specific EN formula, and a standard EN formula in a population of 157 mixed medical-surgical-trauma adult ICU patients. The diabetes-specific formulas provided increased fats compared to the standard formula and also reduced carbohydrate (CHO), which was provided as modified maltodextrin with more resistant starch (the commercial formula provided some CHO as fructose and maltitol). The two diabetes-specific products provided increased lipid as monounsaturated fatty acids and the new formula provided increased omega-3 fatty acids. Calorie goals were based on 25 kcals/kg.

The primary outcome of the study was the amount of insulin required to maintain blood glucose within the range of 110-150 mg/dl. Secondary endpoints were glycemic control (plasma and capillary blood glucose, glycemic variability), ICU-acquired infections, days on mechanical ventilation, ICU stay, and mortality at 28 days post admission. Patients were followed for 6 months post-discharge to record hospital stay, hospital mortality, and 6-month mortality. Hypoglycemia was defined as blood glucose < 50 mg/dl and “moderate hypoglycemia” was defined as blood glucose 50-80 mg/dl.

Inclusion and Exclusion Criteria:

Inclusion criteria:

Age ≥18 years, ICU stay ≤48 hours prior to randomization, receiving mechanical ventilation, EN indicated for an expected time ≥5 days, met criteria for diabetes/hyperglycemia (baseline fasting blood glucose >126 mg/dL or >200 mg/dL unfasted) in the first 48 h of ICU admission.

Exclusion criteria:

Contraindication to EN or EN expected <5 days, APACHE II score ≤10, insulin-dependent diabetes, acute or chronic kidney injury, hepatic failure, life expectancy ≤48 h, previous cardiac arrest, long-term therapy with corticosteroid, immunosuppressant or lipid-lowering drugs, pregnancy, body mass index (BMI) ≥40, or parenteral nutrition (PN).

Major Results:

There were 6280 patients screened for study eligibility, with 4820 excluded due to PN use and 1304 ineligible due to other exclusion criteria. Ultimately, data from 157 patients were analyzed. There were no glaring imbalances between baseline characteristics among the groups and the mean BMI was 26 kg/m². The amounts of propofol and intravenous dextrose calories received were not stated, but the authors reported that all intravenous calories were included in the total calories received.

EN was started 23-27 hours after ICU admission, and average calorie delivery was 21-22 kcals/kg with no significant differences between groups. The amount of insulin administered to patients receiving the new EN formula was 19.1 units/24 hours, which was statistically significantly less than that administered to the standard EN group (23.7 units/24 hours) and not statistically different that that given to the commercial diabetes-specific EN formula group (20.3 units/24 hours). Mean plasma glucose level was 138.6 mg/dl in the patients receiving the new EN formula, which was statistically significantly less than the plasma glucose of the standard EN group (146.1 mg/dl) but not statistically different that the plasma glucose of the commercial diabetes-specific EN formula group (143.9 mg/dl). There was no significant difference in the incidence of hypoglycemia, but patients in the standard EN formula group had a significantly greater incidence of what was described as “moderate hypoglycemia” than either of the diabetes-specific formula groups. Glucose lability index was significantly greater in the standard EN formula group compared to both diabetes-specific groups and glycemic variability was significantly greater in the standard formula compared only to the new EN formula group.

There was no significant difference in total infections, bloodstream infections, or urinary tract infections between the groups. Tracheobronchitis incidence per 1000 ventilator days occurred in 10/392 in the standard EN group, 7/460 patients in the new EN group, and 7/424 in the commercial diabetes-specific EN group, which was statistically significantly greater in the standard group compared to both glucose specific groups. Ventilator-associated pneumonia/1000 ventilator days occurred in 10/392 in the standard EN group, 8/460 patients in the new EN group and 6/424 in the commercial glucose-specific EN group, which was statistically significantly greater in the standard groups compared to both glucose specific groups. There were no significant differences in days requiring insulin treatment, on mechanical ventilation, in the ICU, or hospital, and no difference in 28-day or 6-month mortality.

Author’s Conclusions:

The use of a high-protein diabetes-specific EN formula in hyperglycemic critically ill patients on mechanical ventilation leads to lower insulin requirements, reduces plasma and capillary blood glucose levels and glycemic variability, and could also reduce the risks of ICU- acquired ventilator-associated pneumonia and tracheobronchitis when compared with a standard formula. These results highlight the need for double-blind studies with glycemic variability as the primary endpoint in large critically ill patient populations.

Evaluation:

The strong points of this study include the multicenter design and the fact that patients were randomized to a feeding formula in a way that would not allow the researchers to know ahead of time which formula a potential subject would receive (concealed allocation). However, this study did not have a double-blind design, which is especially important when evaluating endpoints with a subjective component (such as VAP). Additionally, the study had statistical power to detect significant differences in insulin administration, but was far too small to reliably study outcomes such as mortality or length of stay in a diverse group of critically ill patients. It is difficult to know if the differences in outcomes such as VAP and trachobronchitis were from chance alone, because there was only a difference between 2-4 cases between groups.

Although the required dose of insulin and the mean blood glucose were statistically greater in the standard EN group, these differences appear to be clinically trivial. The standard EN group only required 4.6 units of insulin more/day than the new formula group, and 3.4 units/day more than the commercial diabetes-specific formula group. Mean plasma glucose was less than 10 mg/dl different between groups. True hypoglycemia was uncommon and not significantly different between groups, and there are not clear clinical implications of “moderate hypoglycemia”. The differences in glucose variability do deserve further study. Observational studies have documented an association between glucose variability and worse outcomes in the ICU, however, at present, there is no way to know if the increased glucose variability is the cause, or merely an artifact of a compromised ICU course.

Specialized formulas generally cost substantially more per calorie than standard products, and we should good data that demonstrates medical and cost effectiveness before using any specialized products.

Our Take Home Message(s)

In critically ill adult patients receiving continuous tube feeding, diabetes-specific EN formulas have clinically trivial effects on insulin requirements and mean blood glucose.
Larger double-blind studies will be needed to determine if there are outcome improvements related to decreasing glucose variability or the incidence of moderate hypoglycemia with specialized EN formulas.

Other News on the UVAHS GI Nutrition Website: (www.GInutrition.virginia.edu):

Upcoming Webinars 2016:

Tuesday, September 20: Small Intestinal Bacterial Overgrowth (SIBO, aka SBBO)

Wednesday, November 16: Essential Fatty Acid Deficiency

December (date TBA): Fluids in the ICU

Latest Practical Gastroenterology articles:

Kirby JL, O’Donnell K. Hyperinsulinemic Hypoglycemia After Gastric Bypass Surgery. Practical Gastroenterology 2016;XL(6):36.
Han Z, Margulies SL, Kirian D, et al. Vitamin D Deficiencies in Patients with Disorders of the GI System: Current Knowledge and Practical Considerations. Practical Gastroenterology 2016;XL(7):36.

Joe Krenitsky MS, RDN

PS – Please feel free to forward on to friends and colleagues.