University of Virginia Nutrition
We completed another great traineeship week, with trainees visiting from Richmond, Newport News, Boone, NC, and Singapore!
Our journal club article this month is a "high-impact" article- the study of intensive insulin therapy in the medical ICU. It has been a little daunting to write up because the results of this study have been somewhat controversial, resulting in different "take-home" messages for clinical practice from various experts. This month, please keep in mind that there is absolutely no way to cover every aspect of this study that deserves discussion, AND still keep this concise and readable.
As always, we recommend that you read the full study, but with this study in particular we highly recommend that you read the editorial in the February 2 issue1 and the letters to the editor and investigator's response in the May 11 issue 2 of NEJM. We also found it helpful to re-review the 2001 study of intensive insulin in a primarily surgical population.3
References to above:
1) Malhotra A. N Engl J Med. 2006;2;354(5):516-8.
2) N Engl J Med. 2006;354(19):2069-71; author reply 2069-71.
Van den Berghe G, Wilmer A, Hermans G, et al. Intensive Insulin Therapy in the Medical ICU. N Engl J Med 2006;354:449-61.
This was a randomized, controlled trial of adult patients admitted to a medical ICU expected to require intensive care for at least three days. Patients were randomly assigned to strict normalization of blood glucose levels (insulin infusion when blood glucose level exceeded 110 mg/dl) to maintain blood glucose between 80-110 mg/dl, vs. conventional therapy (insulin infusion when blood glucose level exceeded 215 mg/dl to maintain blood glucose between 180-200 mg/dl). The rate of insulin infusion was adjusted at 1-4 hour intervals.
Major Results reported by authors:
In the analysis of 1200 patients, intensive insulin therapy did not significantly reduce in-hospital mortality (40% in the conventional-treatment group vs. 37% in the intensive-treatment group, p = 0.33). However, morbidity was significantly reduced by the prevention of newly acquired kidney injury, accelerated weaning from mechanical ventilation, and accelerated discharge from the ICU and the hospital.
In the 433 patients that stayed in the ICU for less than three days, mortality was greater among those receiving intensive insulin therapy (56 of 209 [27%] intensive vs 42 of 224 [19%] conventional). Hypoglycemia also occurred more often in the intensive insulin group (111 [18.7%] intensive vs 19 [3.1%] conventional p < 0.001). However, among 767 patients who stayed in the ICU for > 3 days, in-hospital mortality in those who received intensive insulin therapy was significantly reduced from 52 to 43% (p = 0.009).
Intensive insulin therapy significantly reduced morbidity but not mortality among all patients in the medical ICU. However, intensive insulin therapy in patients who stayed in the ICU for at least 3 days was associated with reduced morbidity and mortality. Large multicenter trials are needed to confirm these preliminary results.
The group was impressed by the differences between the current study and the study published by the same investigators in 2001 study with surgical patients. One of the most conspicuous differences between the populations in these two studies was the overall mortality rate. The overall hospital mortality of the surgical population from the 2001 study was 9%, while the mortality of the 1200 medical ICU patients in the current study was 39%.
The lack of a mortality advantage in the primary endpoint (overall hospital mortality), along with the increased mortality in those that stayed in the ICU for less than 3 days raises concerns. Although there may be a benefit those patients that stayed for a longer period in the ICU, there are some confounding factors that must be considered. There is a selection bias in the group that stayed greater than 3 days in the ICU; it is possible that those that might potentially be harmed by early intensive insulin therapy (sickest, those subject to severe hypoglycemia, etc) would have expired thus "stacking the odds" in favor of those who survived (and benefit from intensive insulin). There is no way to know if the mortality benefit in those staying greater than 3 days was purely a beneficial effect of intensive insulin, or was influenced by other selection bias into that group (> 3 day ICU stay).
One difference between the methods of the 2001 study and the current one that has not received adequate attention is the difference in the nutrition regimen. In the 2001 study all patients were placed on a glucose infusion of 200-300g/24 hours (680-1020 calories) on admission and the next day patients received 20-30 nonprotein calories per kg. In the present study, patients did not receive the glucose infusion and the ultimate calorie goals were less because they were based on 22-30 total calories per kg. Patients received minimal calories for the first 12 hours, less than 800 nonprotein calories on day 1, and did not receive full calories until day 3-4. One must consider the possibility that it may be detrimental to administer intensive insulin therapy before patients receive adequate nutrition. There is limited data about the amount of enteral nutrition provided during the study. It appears that most patients did not receive even ½ of their calorie needs enterally before day 8 (!!) of the study, additionally, there is no report of the frequency (or days) of TPN use between the two groups.
Another issue that was raised during our journal club was the modest hyperglycemia of the control group. The control group was treated quite unlike "conventional practice" of glucose control at many facilities. The conventional practice group in the study received a continuous insulin infusion with frequent glucose checks, and overall quite reasonable (under 180mg/dl) glucose control. All of those present at the journal club worked at facilities where the reality of "conventional" glucose control means sliding scale insulin every 6 hours with serum glucoses running 200-300mg/dl (this is a frequent admission reported by many that have attended our traineeship). It may be that much of the benefit of intensive insulin therapy was already realized by the control group, thus the failure to find any significant difference in bacterial infections or antibiotic use, even among those that stayed in the ICU for a longer period. Several experts have suggested that it is possible that the favorable balance (equipoise) between the benefits and risks of intensive insulin therapy may be realized at a serum glucose level between 120-150mg/dl rather than a protocol to maintain glucose between 80-110mg/dl.
Take home message:
This study raises a number of questions and several concerns. Additional studies are clearly needed, and if you read the letters to the editor in the May NEJM and replies to the letters you realize that there is no universal agreement yet on the best course in medical ICU patients. The take home opinion of the group is that we would all rather have a insulin infusion and frequent glucose checks rather than sliding scale insulin and glucoses of 300mg/dl if we were in the ICU, with a few caveats....we might choose to delay VERY intensive insulin therapy until we are receiving adequate nutrition, especially in those patients prone to hypoglycemia (malnutrition, renal failure, end-stage liver disease), until further data is available.
We hope all of you had an adequate calorie intake (and good glucose control) on Turkey-day! ...we don't even want to imagine what your residuals might be !!!
1) Weekend Warrior Mini-Nutrition Support Traineeship is coming!
When: Weekend of March 10th and 11th, 2007. Watch our website below for details in the near future:
2) Check out the latest Practical Gastroenterology articles/info at:
Scroll down to GI Nutrition on the far left column and click on link
Then scroll down to box with links within the nutrition site
Nutrition Articles in Practical Gastroenterology is in the right column:
1) Condron S. Post-PEG Feeding - Why Wait? Practical Gastroenterology 2006;XXX(11):48.
2) Cureton P. Dining Out Gluten Free: Is it Safe? Practical Gastroenterology 2006;XXX(11):61.
Joe Krenitsky MS, RD
Carol Parrish RD, MS
PS - Please feel free to forward this on to friends and colleagues.