March 2011 E-Journal Club


Things have been busier than usual around here lately.  After 150 years of written medical charts and 25 years of the same computer system for labs and orders, UVA implemented a new electronic medical record and documentation system.  We are still adapting to our brave new world, but did manage to find time for journal club.  We also hosted a great group for a Weekend Warrior program in March as pictured above.

March Citation: 

Arabi YM, Tamim HM, Dhar GS, Al-Dawood A, Al-Sultan M, Sakkijha MH, Kahoul SH, Brits R.  Permissive underfeeding and intensive insulin therapy in critically ill patients: a randomized controlled trial.  Am J Clin Nutr. 2011;93(3):569-77.


This was a randomized, unblinded study of patients in a mixed medical-surgical ICU where patients were assigned to 1 of 4 groups: permissive underfeeding with intensive insulin therapy, permissive underfeeding with conventional insulin therapy, full nutrition with intensive insulin therapy, or full nutrition with conventional insulin therapy.  Goal calorie needs were defined as 90-100% of energy expenditure estimated by Harris-Benedict equation with unspecified stress factors.  Permissive underfeeding was defined as 60-70% of estimated energy expenditure.  Protein needs were calculated as “0.8-1.5 g/kg on the basis of patient condition and underlying diseases.”  The hypocaloric feeding group received protein supplements as needed to meet the calculated protein goal. The target blood glucose concentration of the intensive insulin treatment (IIT) group was 4.4-6.1 mmol/L (80-110mg/dL) and 10-11.1mmol/L (180-200 mg/dL) in the conventional insulin treatment (CIT) group.

The primary endpoint of the study was 28 day all-cause mortality.  Secondary endpoints included ICU, hospital, and 180-day mortality, ICU and hospital length of stay; and duration of mechanical ventilation.  Investigators also documented infections up to 48 h after ICU discharge, the need for renal replacement therapy, packed red blood cell transfusion and the occurrence of hypoglycemia and hypokalemia.

Inclusion and Exclusion Criteria were:

Inclusion criteria:

  • Age ≥ 18 years
  • Blood glucose concentration >6.1 mmol/L (110 mg/dL)
  • Receiving enteral feeding
  • Expected stay ≥48 h

Exclusion criteria:

  • Type 1 diabetes or diabetic ketoacidosis
  • Hypoglycemia
  • Brain death
  • Do-not-resuscitate status
  • Terminal illness
  • Postcardiac arrest
  • Seizures within the past 6 mo
  • Pregnancy
  • Liver transplant
  • Burn injury
  • Readmission to the ICU within the same hospitalization or enrollment in a competing trial
  • Receiving oral feeding or total parenteral nutrition.

Major Results reported by authors:

The investigators ultimately randomized the 240 patients as follows:

  1. 61 patients target feeding/intensive insulin
  2. 59 patients target feeding/conventional insulin
  3. 59 patients hypocaloric feeding/intensive insulin
  4. 61 patients hypocaloric feeding/conventional insulin

All analysis was conducted on an intention-to-treat basis.  The authors reported that they tested for interactions between the 2 different interventions (insulin and calories) with multivariate logistic regression modeling and found no statistically significant interaction between the two interventions. Therefore, investigators then decided to combine the data from the permissive underfeeding groups, regardless of insulin group assignment.  Likewise the data from those receiving goal calorie feeding was combined from conventional and intensive insulin therapy groups for the analysis.

In the analysis of how much nutrition was actually provided to the patients, those in the permissive underfeeding group received 59.0 ± 16.1% of calculated goal nutrition, while those in the target feeding group received 71.4 ± 22.8% of goal.

There were no significant differences in the primary outcome between the conventional and intensive insulin groups. The only secondary endpoint that was different between the insulin groups was hypoglycemia, which was significantly greater in the intensive insulin group (31.7% vs 6.7%, p< 0.0001).

In the calorie groups there was no significant difference in the primary outcome of 28-day mortality (18.3% permissive underfeeding group Vs 23.3% target feeding group, RR: 0.79; 95% CI: 0.48, 1.29; P = 0.34).  Of the secondary outcomes, 3 out of the 20 variables listed were significantly different between the groups.  Hospital mortality was significantly lower in the permissive underfeeding group than in the target feeding group (30.0% Vs 42.5%; RR: 0.71; 95% CI: 0.50, 0.99; P = 0.04).  The permissive underfeeding group required significantly less packed red cell transfusions than the target group (0.07 ± 0.16 Vs 0.12 ± 0.24 units/d; P = 0.03), and also had significantly less hypokalemic episodes (7.5% of patients compared with 19.2% of patients; P = 0.008).  Additionally there appeared to be a trend towards decreased 180-day mortality (32.8% permissive underfeeding Vs 44.4% target feeding group, RR: 0.74; 95% CI: 0.53, 1.03; P = 0.07).

Author’s Conclusions:

The authors reported in the discussion section that, “the main finding in our study was that permissive underfeeding was associated with lower morbidity and mortality than was target feeding in critically ill patients. IIT was not associated with an improvement in outcomes relative to CIT”.  The final conclusion was that, permissive underfeeding may be associated with lower mortality than target feeding in critically ill patients, and that a larger multicenter study be conducted to confirm these findings.”


This study attempts to addresses an unanswered core question for ICU nutrition support – the benefit or potential harm of providing full calories to critically ill patients.  The strong points of this study include the randomized design, use of protein supplements to keep the groups isonitrogenous, exclusion of all TPN during the study, providing data on the amount of nutrition that was actually received by the patients, and analysis according to intention to treat.  In addition, the patient characteristics suggest that the groups were relatively similar after randomization.

However, there are a number of considerations that our group discussed when we critiqued this study.  The most notable was that the two groups actually received very similar calorie provision.  Although the calorie provision was statistically different, the mean difference in calorie provision between the 2 groups did not appear to be clinically different – only 185 calories/day.  This study, yet again, highlights the difficulty of consistently meeting patient calorie goals; regardless of the accuracy of your initial prediction equation, even when you have nutrition professionals adjusting the feedings daily to help meet goals.

Another major issue in this study was the relatively small number of patients (120 patients/group) for the study of heterogenous (medical, surgical, trauma, brain injured, etc.) critically ill patients with mortality as the primary outcome.  Certainly these numbers are too small to allow meaningful analysis of any subgroups (obese, lean, elderly, malnourished) that might have had a more negative (or positive) response to hypocaloric feedings.  It is notable than the mean BMI of the groups was 28.5 +/- 8, which suggests that some patients were obese and may have had greater benefit from hypocaloric nutrition; or, perhaps more detrimental effects of full nutrition.  Although hospital mortality was significantly less in the hypocaloric group, considering that a number of secondary factors were measured, it is possible that this is a chance statistical difference.

The last major concern is the combination of groups in a 2X2 factorial design study.  Although there was no statistically significant interaction between the groups (glucose vs. calorie) there does appear to be certain patients (medical, hepatic or renal failure) who appear to be more at risk for negative effects of achieving normoglycemia with intensive insulin.  In a study with modest numbers of patients the concern would be that the “noise” from different responses to tight glucose control might obscure a response to different nutrition regimens.  There were other more minor issues and bits of wisdom that we don’t have space for here – as always, we encourage you to read the whole article too.

Our Take Home messages:

Hypocaloric, full protein feedings may offer a survival advantage in critical illness. There is a need for a large multi-center study of hypocaloric, full-protein, full-micronutrient nutrition support (metabolic support) (1) in critical illness that excludes patients with low BMI and malnutrition.


  • 1) Burke PA, Young LS, Bistrian BR. Metabolic vs. nutrition support: a hypothesis. JPEN 2010;34(5):546-8.

Other News:

See our website: for:

Upcoming Webinars for Spring/Summer 2011:

  • April 12: Enteral Nutrition in the Critically Ill Pediatric Patient–Ana Abad-Jorge, MS, RD, CNSC
  • May 24: Gastric versus Jejunal Feeding:Combining Data and Clinical Judgment—Joe Krenitsky, MS, RD
  • June 14: Small Bowel Bacterial Overgrowth–Carol Parrish, MS, RD
  • July 19: Feeding the Post-Surgical Patient–Kate Willcutts, MS, RD, CNSC

Latest Practical Gastroenterology articles:

  • Gurram K. Nasal Bridle: married to your tube. Practical Gastroenterology 2011;XXXV(1):27-34.
  • Wittenbrook W. Nutritional Assessment and Intervention in Cerebral Palsy. Practical Gastroenterology 2011;XXXV(2):16-32.