Dieter Mesotten

Early versus Late Parenteral Nutrition in Critically Ill Adults

BACKGROUND Controversy exists about the timing of the initiation of parenteral nutrition in critically ill adults in whom caloric targets cannot be met by enteral nutrition alone. METHODS In this randomized, multicenter trial, we compared early initiation of parenteral nutrition (European guidelines) with late initiation (American and Canadian guidelines) in adults in the intensive care unit (ICU) to supplement insufficient enteral nutrition. In 2312 patients, parenteral nutrition was initiated within 48 hours after ICU admission (early-initiation group), whereas in 2328 patients, parenteral nutrition was not initiated before day 8 (late-initiation group). A protocol for the early initiation of enteral nutrition was applied to both groups, and insulin was infused to achieve normoglycemia. RESULTS Patients in the late-initiation group had a relative increase of 6.3% in the likelihood of being discharged alive earlier from the ICU (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.13; P=0.04) and from the hospital (hazard ratio, 1.06; 95% CI, 1.00 to 1.13; P=0.04), without evidence of decreased functional status at hospital discharge. Rates of death in the ICU and in the hospital and rates of survival at 90 days were similar in the two groups. Patients in the late-initiation group, as compared with the early-initiation group, had fewer ICU infections (22.8% vs. 26.2%, P=0.008) and a lower incidence of cholestasis (P<0.001). The late-initiation group had a relative reduction of 9.7% in the proportion of patients requiring more than 2 days of mechanical ventilation (P=0.006), a median reduction of 3 days in the duration of renal-replacement therapy (P=0.008), and a mean reduction in health care costs of €1,110 (about

Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients

1,600) (P=0.04). CONCLUSIONS Late initiation of parenteral nutrition was associated with faster recovery and fewer complications, as compared with early initiation. (Funded by the Methusalem program of the Flemish government and others; EPaNIC ClinicalTrials.gov number, NCT00512122.).

Acute outcomes and 1-year mortality of intensive care unit-acquired weakness. A cohort study and propensity-matched analysis

BACKGROUND Maintenance of normoglycaemia by use of insulin reduces morbidity and mortality of patients in surgical intensive care. Studies on mitochondrial function in critical illness or diabetes suggest that effects of intensive insulin therapy on mitochondrial integrity contribute to the clinical benefits. METHODS Enzyme activities of the respiratory-chain complexes and oxidative-stress-sensitive glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were measured by spectrophotometry in 36 snap-frozen samples of liver and skeletal muscle obtained after death from patients who had been randomly assigned intensive (normoglycaemia) or conventional (hyperglycaemia) insulin therapy and who were similar in terms of admission diagnoses and causes of death. Mitochondrial ultrastructure was examined by electron microscopy in a random subgroup (n=20). FINDINGS In the liver, hypertrophic mitochondria with an increased number of abnormal and irregular cristae and reduced matrix electron density were observed in seven of nine conventionally treated patients. Only one of 11 patients given intensive insulin treatment had these morphological abnormalities (p=0.005). The effect on ultrastructure was associated with higher activities of respiratory-chain complex I (median 1.53 [IQR 1.14-3.01] vs 0.81 [0.54-1.43] U/g liver; p=0.008) and complex IV (1.69 [1.40-1.97] vs 1.16 [0.97-1.40] U/g; p=0.008) in the intensive group than in the conventional group. There was no detectable difference in GAPDH activity. In skeletal muscle, mitochondrial ultrastructure and function were not affected by intensive insulin therapy. INTERPRETATION Strict glycaemic control with intensive insulin therapy prevented or reversed ultrastructural and functional abnormalities of hepatocyte mitochondria. The lack of effect on skeletal-muscle mitochondria suggests a direct effect of glucose toxicity and glucose control, rather than of insulin, as the likely explanation. RELEVANCE TO PRACTICE Maintenance or restoration of mitochondrial function and cellular energetics is another therapeutic target, in addition to optimisation of cardiac output, systemic oxygen delivery, and regional blood flow, that might improve outcome for critically ill patients. Our findings could help to explain the mechanism underlying the reduction in mortality found when normoglycaemia was maintained with insulin, and further support use of intensive insulin therapy in this setting.

Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial

RATIONALE Intensive care unit (ICU)-acquired weakness is a frequent complication of critical illness. It is unclear whether it is a marker or mediator of poor outcomes. OBJECTIVES To determine acute outcomes, 1-year mortality, and costs of ICU-acquired weakness among long-stay (≥8 d) ICU patients and to assess the impact of recovery of weakness at ICU discharge. METHODS Data were prospectively collected during a randomized controlled trial. Impact of weakness on outcomes and costs was analyzed with a one-to-one propensity-score-matching for baseline characteristics, illness severity, and risk factor exposure before assessment. Among weak patients, impact of persistent weakness at ICU discharge on risk of death after 1 year was examined with multivariable Cox proportional hazards analysis. MEASUREMENTS AND MAIN RESULTS A total of 78.6% were admitted to the surgical ICU; 227 of 415 (55%) long-stay assessable ICU patients were weak; 122 weak patients were matched to 122 not-weak patients. As compared with matched not-weak patients, weak patients had a lower likelihood for live weaning from mechanical ventilation (hazard ratio [HR], 0.709 [0.549-0.888]; P = 0.009), live ICU (HR, 0.698 [0.553-0.861]; P = 0.008) and hospital discharge (HR, 0.680 [0.514-0.871]; P = 0.007). In-hospital costs per patient (+30.5%, +5,443 Euro per patient; P = 0.04) and 1-year mortality (30.6% vs. 17.2%; P = 0.015) were also higher. The 105 of 227 (46%) weak patients not matchable to not-weak patients had even worse prognosis and higher costs. The 1-year risk of death was further increased if weakness persisted and was more severe as compared with recovery of weakness at ICU discharge (P < 0.001). CONCLUSIONS After careful matching the data suggest that ICU-acquired weakness worsens acute morbidity and increases healthcare-related costs and 1-year mortality. Persistence and severity of weakness at ICU discharge further increased 1-year mortality. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).

Clinical review: Consensus recommendations on measurement of blood glucose and reporting glycemic control in critically ill adults

BACKGROUND Patients who are critically ill can develop so-called intensive-care unit acquired weakness, which delays rehabilitation. Reduced muscle mass, quality, or both might have a role. The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) trial (registered with ClinicalTrials.gov, number NCT00512122) showed that tolerating macronutrient deficit for 1 week in intensive-care units (late parenteral nutrition [PN]) accelerated recovery compared with early PN. The role of weakness was unclear. Our aim was to assess whether late PN and early PN differentially affect muscle weakness and autophagic quality control of myofibres. METHODS In this prospectively planned subanalysis of the EPaNIC trial, weakness (MRC sum score) was assessed in 600 awake, cooperative patients. Skeletal muscle biopsies, harvested from 122 patients 8 days after randomisation and from 20 matched healthy controls, were studied for autophagy and atrophy. We determined the significance of differences with Mann-Whitney U, Median, Kruskal-Wallis, or χ(2) (exact) tests, as appropriate. FINDINGS With late PN, 105 (34%) of 305 patients had weakness on first assessment (median day 9 post-randomisation) compared with 127 (43%) of 295 patients given early PN (absolute difference -9%, 95% CI -16 to -1; p=0·030). Weakness recovered faster with late PN than with early PN (p=0·021). Myofibre cross-sectional area was less and density was lower in critically ill patients than in healthy controls, similarly with early PN and late PN. The LC3 (microtubule-associated protein light chain 3) II to LC3I ratio, related to autophagosome formation, was higher in patients given late PN than early PN (p=0·026), reaching values almost double those in the healthy control group (p=0·0016), and coinciding with less ubiquitin staining (p=0·019). A higher LC3II to LC3I ratio was independently associated with less weakness (p=0·047). Expression of mRNA encoding contractile myofibrillary proteins was lower and E3-ligase expression higher in muscle biopsies from patients than in control participants (p≤0·0006), but was unaffected by nutrition. INTERPRETATION Tolerating a substantial macronutrient deficit early during critical illness did not affect muscle wasting, but allowed more efficient activation of autophagic quality control of myofibres and reduced weakness. FUNDING UZ Leuven, Research Foundation-Flanders, the Flemish Government, and the European Research Council.

Role of disease and macronutrient dose in the randomized controlled EPaNIC trial: a post hoc analysis.

The management reporting and assessment of glycemic control lacks standardization. The use of different methods to measure the blood glucose concentration and to report the performance of insulin treatment yields major disparities and complicates the interpretation and comparison of clinical trials. We convened a meeting of 16 experts plus invited observers from industry to discuss and where possible reach consensus on the most appropriate methods to measure and monitor blood glucose in critically ill patients and on how glycemic control should be assessed and reported. Where consensus could not be reached, recommendations on further research and data needed to reach consensus in the future were suggested. Recognizing their clear conflict of interest, industry observers played no role in developing the consensus or recommendations from the meeting. Consensus recommendations were agreed for the measurement and reporting of glycemic control in clinical trials and for the measurement of blood glucose in clinical practice. Recommendations covered the following areas: How should we measure and report glucose control when intermittent blood glucose measurements are used? What are the appropriate performance standards for intermittent blood glucose monitors in the ICU? Continuous or automated intermittent glucose monitoring - methods and technology: can we use the same measures for assessment of glucose control with continuous and intermittent monitoring? What is acceptable performance for continuous glucose monitoring systems? If implemented, these recommendations have the potential to minimize the discrepancies in the conduct and reporting of clinical trials and to improve glucose control in clinical practice. Furthermore, to be fit for use, glucose meters and continuous monitoring systems must match their performance to fit the needs of patients and clinicians in the intensive care setting.See related commentary by Soto-Rivera and Agus, http://ccforum.com/content/17/3/155

Early versus late parenteral nutrition in critically Ill children

RATIONALE Early parenteral nutrition to supplement insufficient enteral feeding during intensive care (early PN) delays recovery as compared with withholding parenteral nutrition for 1 week (late PN). OBJECTIVES To assess whether deleterious effects of early PN relate to severity of illness or to the dose or type of macronutrients. METHODS Secondary analyses of a randomized controlled trial (EPaNIC; n = 4,640) performed in seven intensive care units from three departments in two Belgian hospitals. In part 1, all patients were included to assess the effect of the randomized allocation to early PN or late PN in subgroups of patients with increasing-on-admission severity of illness. In part 2, observationally, the association of the amount and type of macronutrients with recovery was documented in those patient cohorts still present in intensive care on Days 3, 5, 7, 10, and 14. MEASUREMENTS AND MAIN RESULTS The primary end point was time to live discharge from the intensive care unit. For part 1, a secondary end point, acquisition of new infections, was also analyzed. All statistical analyses were performed by univariable and adjusted multivariable methods. In none of the subgroups defined by type or severity of illness was a beneficial effect of early PN observed. The lowest dose of macronutrients was associated with the fastest recovery and any higher dose, administered parenterally or enterally, was associated with progressively more delayed recovery. The amount of proteins/amino acids rather than of glucose appeared to explain delayed recovery with early feeding. CONCLUSIONS Early combined parenteral/enteral nutrition delayed recovery irrespective of severity of critical illness. No dose or type of macronutrient was found to be associated with improved outcome. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).

Clinical potential of insulin therapy in critically ill patients.

BACKGROUND Recent trials have questioned the benefit of early parenteral nutrition in adults. The effect of early parenteral nutrition on clinical outcomes in critically ill children is unclear. METHODS We conducted a multicenter, randomized, controlled trial involving 1440 critically ill children to investigate whether withholding parenteral nutrition for 1 week (i.e., providing late parenteral nutrition) in the pediatric intensive care unit (ICU) is clinically superior to providing early parenteral nutrition. Fluid loading was similar in the two groups. The two primary end points were new infection acquired during the ICU stay and the adjusted duration of ICU dependency, as assessed by the number of days in the ICU and as time to discharge alive from ICU. For the 723 patients receiving early parenteral nutrition, parenteral nutrition was initiated within 24 hours after ICU admission, whereas for the 717 patients receiving late parenteral nutrition, parenteral nutrition was not provided until the morning of the 8th day in the ICU. In both groups, enteral nutrition was attempted early and intravenous micronutrients were provided. RESULTS Although mortality was similar in the two groups, the percentage of patients with a new infection was 10.7% in the group receiving late parenteral nutrition, as compared with 18.5% in the group receiving early parenteral nutrition (adjusted odds ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66). The mean (±SE) duration of ICU stay was 6.5±0.4 days in the group receiving late parenteral nutrition, as compared with 9.2±0.8 days in the group receiving early parenteral nutrition; there was also a higher likelihood of an earlier live discharge from the ICU at any time in the late-parenteral-nutrition group (adjusted hazard ratio, 1.23; 95% CI, 1.11 to 1.37). Late parenteral nutrition was associated with a shorter duration of mechanical ventilatory support than was early parenteral nutrition (P=0.001), as well as a smaller proportion of patients receiving renal-replacement therapy (P=0.04) and a shorter duration of hospital stay (P=0.001). Late parenteral nutrition was also associated with lower plasma levels of γ-glutamyltransferase and alkaline phosphatase than was early parenteral nutrition (P=0.001 and P=0.04, respectively), as well as higher levels of bilirubin (P=0.004) and C-reactive protein (P=0.006). CONCLUSIONS In critically ill children, withholding parenteral nutrition for 1 week in the ICU was clinically superior to providing early parenteral nutrition. (Funded by the Flemish Agency for Innovation through Science and Technology and others; ClinicalTrials.gov number, NCT01536275.).

LOGIC-Insulin Algorithm–Guided Versus Nurse-Directed Blood Glucose Control During Critical Illness: The LOGIC-1 single-center, randomized, controlled clinical trial

Stress of critical illness is often accompanied by hyperglycaemia, whether or not the patient has a history of diabetes mellitus. This has been considered to be part of the adaptive metabolic response to stress. The level of hyperglycaemia in patients with acute myocardial infarction (MI) or stroke upon admission to the hospital has been related to the risk of adverse outcome. However, until recently, there was no evidence of a causal relationship and thus stress-induced hyperglycaemia was only treated with exogenous insulin when it exceeded 12 mmol/L (220 mg/dL). In patients with known diabetes, even higher levels were often tolerated. Recently, new data became available in support of another approach. In this review, we focus on the new evidence and the clinical aspects of managing hyperglycaemia with insulin in critically ill patients, drawing a parallel with diabetes management. Particularly, the ‘Diabetes and Insulin-Glucose infusion in Acute Myocardial Infarction (DIGAMI) study’ and the ‘insulin in intensive care study’ have provided novel insights.The DIGAMI study showed that in patients with diabetes, controlling blood glucose levels below 12 mmol/L for 3 months after acute MI improves long-term outcome. In the recent study of predominantly surgical intensive care patients, the majority of whom did not previously have diabetes, it was shown that an even tighter control of blood glucose with exogenous insulin, aiming for normoglycaemia, dramatically improved outcome. Indeed, in this large prospective, randomised, controlled study, 1548 intensive care patients had been randomly allocated to either the conventional approach, with insulin infusion started only when blood glucose levels exceeded 12 mmol/L, or intensive insulin therapy, with insulin infused to maintain blood glucose at a level of 4.5–6.1 mmol/L (80–110 mg/dL).Intensive insulin therapy reduced intensive care mortality by more than 40% and also decreased a number of morbidity factors including acute renal failure, polyneuropathy, ventilator-dependency and septicaemia.Future studies will be needed to further unravel the mechanisms that explain the beneficial effects of this simple and cost-saving intervention. Although available evidence supports implementation of intensive insulin therapy in surgical intensive care, the benefit for other patient populations, such as patients on medical intensive care units or hospitalised patients who do not require intensive care but who do present with stress-induced hyperglycaemia, remains to be investigated.

Impact of early parenteral nutrition on muscle and adipose tissue compartments during critical illness.

OBJECTIVE Tight blood glucose control (TGC) in critically ill patients is difficult and labor intensive, resulting in poor efficacy of glycemic control and increased hypoglycemia rate. The LOGIC-Insulin computerized algorithm has been developed to assist nurses in titrating insulin to maintain blood glucose levels at 80–110 mg/dL (normoglycemia) and to avoid severe hypoglycemia (<40 mg/dL). The objective was to validate clinically LOGIC-Insulin relative to TGC by experienced nurses. RESEARCH DESIGN AND METHODS The investigator-initiated LOGIC-1 study was a prospective, parallel-group, randomized, controlled clinical trial in a single tertiary referral center. A heterogeneous mix of 300 critically ill patients were randomized, by concealed computer allocation, to either nurse-directed glycemic control (Nurse-C) or algorithm-guided glycemic control (LOGIC-C). Glycemic penalty index (GPI), a measure that penalizes both hypoglycemic and hyperglycemic deviations from normoglycemia, was the efficacy outcome measure, and incidence of severe hypoglycemia (<40 mg/dL) was the safety outcome measure. RESULTS Baseline characteristics of 151 Nurse-C patients and 149 LOGIC-C patients and study times did not differ. The GPI decreased from 12.4 (interquartile range 8.2–18.5) in Nurse-C to 9.8 (6.0–14.5) in LOGIC-C (P < 0.0001). The proportion of study time in target range was 68.6 ± 16.7% for LOGIC-C patients versus 60.1 ± 18.8% for Nurse-C patients (P = 0.00016). The proportion of severe hypoglycemic events was decreased in the LOGIC-C group (Nurse-C 0.13%, LOGIC-C 0%; P = 0.015) but not when considered as a proportion of patients (Nurse-C 3.3%, LOGIC-C 0%; P = 0.060). Sampling interval was 2.2 ± 0.4 h in the LOGIC-C group versus 2.5 ± 0.5 h in the Nurse-C group (P < 0.0001). CONCLUSIONS Compared with expert nurses, LOGIC-Insulin improved efficacy of TGC without increasing rate of hypoglycemia.