Early Enteral Permissive Underfeeding in Critically Ill Young Adults with Traumatic Brain Injury: A Single-Blind Randomized Controlled Pilot Trial

Background and Objectives: There is no consensus on optimal initial energy requirements for critically ill patients. The present study aimed to compare the clinical outcomes of early enteral permissive underfeeding (EEPU) with those of early enteral standard feeding (EESF) in critically ill patients with traumatic brain injury (TBI). Materials and Methods: In this single-blind, randomized, controlled pilot trial, 60 young adults with TBI were randomly assigned to either EESF or EEPU groups (initiation energy goal: 100% vs. 30% of estimated energy requirements, respectively). Enteral feeding was administered during 24-48 hours of intensive care unit admission. Patients receiving EEPU were prescribed to achieve full energy requirements by day seven of the intervention. Results: The EEPU group demonstrated improved glycemic control (205.6±68 vs. 137.4±59 mg/dL, P=0.02), reduced duration of hospital stay (57.5±29 vs. 70.9±24 days, P=0.08) and shorter duration of mechanical ventilation (20.2±11 vs. 26.4±9 days, P=0.04). Gastrointestinal complications were more frequent in the EESF group (3.5±2 vs. 1.4±3 days, P=0.001). There were no differences between the EESF and EEPU groups in terms of 28-day mortality rate (3.8% vs. 10.7%, RR: 0.33; 95% CI: 0.03, 3.42; P=0.61).Conclusion: EEPU may be associated with beneficial effects on gastrointestinal toleration and glycemic control in young TBI patients, which might contribute to improved clinical outcomes in this population; however, further investigations are required on this issue. Trial registration: This trial was registered at Iranian Registry of Clinical Trials (www.irct.ir) as IRCT201201128709N1.

Leptin, Ghrelin, and Leptin/Ghrelin Ratio in Critically Ill Patients

The objective of this study was to evaluate leptin, ghrelin, and leptin/ghrelin ratio in critically ill patients and association of leptin/ghrelin ratio with outcomes. This is a sub-study of the PermiT trial (ISRCTN68144998). A subset of 72 patients who were expected to stay >14 days in the Intensive care unit were enrolled. Blood samples were collected on days 1, 3, 5, 7, and 14. Samples were analyzed for leptin and active ghrelin in addition to other hormones. Baseline leptin/ghrelin ratio was calculated, and patients were stratified into low and high leptin/ghrelin ratio based on the median value of 236. There was a considerable variation in baseline leptin level: Median 5.22 ng/mL (Q1, Q3: 1.26, 17.60). Ghrelin level was generally low: 10.61 pg/mL (Q1, Q3: 8.62, 25.36). Patients with high leptin/ghrelin ratio compared to patients with low leptin/ghrelin ratio were older, had higher body mass index and more likely to be diabetic. There were no differences in leptin/ghrelin ratio between patients who received permissive underfeeding and standard feeding. Multivariable logistic regression analysis showed that age and body mass index were significant independent predictors of high leptin–ghrelin ratio. Leptin–ghrelin ratio was not associated with 90-day mortality or other outcomes. Age and body mass index are predictors of high leptin/ghrelin ratio. Leptin/ghrelin ratio is not affected by permissive underfeeding and is not associated with mortality.

Effect of Permissive Underfeeding with Intensive Insulin Therapy on MCP-1, sICAM-1, and TF in Critically Ill Patients

Purpose: This study examined the effect of permissive underfeeding compared to target feeding and intensive insulin therapy (IIT) compared to conventional insulin therapy (CIT) on the inflammatory mediators monocyte chemoattractant protein 1 (MCP-1), soluble intercellular adhesion molecule 1 (sICAM-1), and tissue factor (TF) in critically ill patients. Methodology: This was a substudy of a 2 × 2 factorial design randomized controlled trial in which intensive care unit (ICU) patients were randomized into permissive underfeeding compared to target feeding groups and into IIT compared to CIT groups (ISRCTN96294863). In this substudy, we included 91 patients with almost equal numbers across randomization groups. Blood samples were collected at baseline and at days 3, 5, and 7 of an ICU stay. Linear mixed models were used to assess the differences in MCP-1, sICAM-1, and TF across randomization groups over time. Results: Baseline characteristics were balanced across randomization groups. Daily caloric intake was significantly higher in the target feeding than in the permissive underfeeding groups (P-value < 0.01), and the daily insulin dose was significantly higher in the IIT than in the CIT groups (P-value < 0.01). MCP-1, sICAM-1, and TF did not show any significant difference between the randomization groups, while there was a time effect for MCP-1. Baseline sequential organ failure assessment (SOFA) score and platelets had a significant effect on sICAM-1 (P-value < 0.01). For TF, there was a significant association with age (P-value < 0.01). Conclusions: Although it has been previously demonstrated that insulin inhibits MCP-1, sICAM-1 in critically ill patients, and TF in non-critically ill patients, our study demonstrated that IIT in critically ill patients did not affect these inflammatory mediators. Similarly, caloric intake had a negligible effect on the inflammatory mediators studied.

Free Fatty Acids’ Level and Nutrition in Critically Ill Patients and Association with Outcomes: A Prospective Sub-Study of PermiT Trial

Objectives: The objectives of this study were to evaluate the clinical and nutritional correlates of high free fatty acids (FFAs) level in critically ill patients and the association with outcomes, and to study the effect of short-term caloric restriction (permissive underfeeding) on FFAs level during critical illness. Patients/Method: In this pre-planned sub-study of the PermiT (Permissive Underfeeding vs. Target Enteral Feeding in Adult Critically Ill Patients) trial, we included critically ill patients who were expected to stay for ≥14 days in the intensive care unit. We measured FFAs level on day 1, 3, 5, 7, and 14 of enrollment. Of 70 enrolled patients, 23 (32.8%) patients had high FFAs level (baseline FFAs level >0.45 mmol/L in females and >0.6 mmol/L in males). Results: Patients with high FFAs level were significantly older and more likely to be females and diabetics and they had lower ratio of partial pressure of oxygen to the fraction of inspired oxygen, higher creatinine, and higher total cholesterol levels than those with normal FFAs level. During the study period, patients with high FFAs level had higher blood glucose and required more insulin. On multivariable logistic regression analysis, the predictors of high baseline FFAs level were diabetes (adjusted odds ratio (aOR): 5.36; 95% confidence interval (CI): 1.56, 18.43, p = 0.008) and baseline cholesterol level (aOR, 4.29; 95% CI: 11.64, 11.19, p = 0.003). Serial levels of FFAs did not differ with time between permissive underfeeding and standard feeding groups. FFAs level was not associated with 90-day mortality (aOR: 0.49; 95% CI: 0.09, 2.60, p = 0.40). Conclusion: We conclude that high FFAs level in critically ill patients is associated with features of metabolic syndrome and is not affected by short-term permissive underfeeding.