Greet Hermans

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

Early exercise in critically ill patients enhances short-term functional recovery*

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.).

Clinical review: Critical illness polyneuropathy and myopathy

Objectives:To investigate whether a daily exercise session, using a bedside cycle ergometer, is a safe and effective intervention in preventing or attenuating the decrease in functional exercise capacity, functional status, and quadriceps force that is associated with prolonged intensive care unit stay. A prolonged stay in the intensive care unit is associated with muscle dysfunction, which may contribute to an impaired functional status up to 1 yr after hospital discharge. No evidence is available concerning the effectiveness of an early exercise training intervention to prevent these detrimental complications. Design:Randomized controlled trial. Setting:Medical and surgical intensive care unit at University Hospital Gasthuisberg. Patients:Ninety critically ill patients were included as soon as their cardiorespiratory condition allowed bedside cycling exercise (starting from day 5), given they still had an expected prolonged intensive care unit stay of at least 7 more days. Interventions:Both groups received respiratory physiotherapy and a daily standardized passive or active motion session of upper and lower limbs. In addition, the treatment group performed a passive or active exercise training session for 20 mins/day, using a bedside ergometer. Measurements and Main Results:All outcome data are reflective for survivors. Quadriceps force and functional status were assessed at intensive care unit discharge and hospital discharge. Six-minute walking distance was measured at hospital discharge. No adverse events were identified during and immediately after the exercise training. At intensive care unit discharge, quadriceps force and functional status were not different between groups. At hospital discharge, 6-min walking distance, isometric quadriceps force, and the subjective feeling of functional well-being (as measured with “Physical Functioning” item of the Short Form 36 Health Survey questionnaire) were significantly higher in the treatment group (p < .05). Conclusions:Early exercise training in critically ill intensive care unit survivors enhanced recovery of functional exercise capacity, self-perceived functional status, and muscle force at hospital discharge.

Increased duration of mechanical ventilation is associated with decreased diaphragmatic force: a prospective observational study

Critical illness polyneuropathy (CIP) and myopathy (CIM) are major complications of severe critical illness and its management. CIP/CIM prolongs weaning from mechanical ventilation and physical rehabilitation since both limb and respiratory muscles can be affected. Among many risk factors implicated, sepsis, systemic inflammatory response syndrome, and multiple organ failure appear to play a crucial role in CIP/CIM. This review focuses on epidemiology, diagnostic challenges, the current understanding of pathophysiology, risk factors, important clinical consequences, and potential interventions to reduce the incidence of CIP/CIM. CIP/CIM is associated with increased hospital and intensive care unit (ICU) stays and increased mortality rates. Recently, it was shown in a single centre that intensive insulin therapy significantly reduced the electrophysiological incidence of CIP/CIM and the need for prolonged mechanical ventilation in patients in a medical or surgical ICU for at least 1 week. The electrophysiological diagnosis was limited by the fact that muscle membrane inexcitability was not detected. These results have yet to be confirmed in a larger patient population. One of the main risks of this therapy is hypoglycemia. Also, conflicting evidence concerning the neuromuscular effects of corticosteroids exists. A systematic review of the available literature on the optimal approach for preventing CIP/CIM seems warranted.

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

IntroductionRespiratory muscle weakness is an important risk factor for delayed weaning. Animal data show that mechanical ventilation itself can cause atrophy and weakness of the diaphragm, called ventilator-induced diaphragmatic dysfunction (VIDD). Transdiaphragmatic pressure after magnetic stimulation (TwPdi BAMPS) allows evaluation of diaphragm strength. We aimed to evaluate the repeatability of TwPdi BAMPS in critically ill, mechanically ventilated patients and to describe the relation between TwPdi and the duration of mechanical ventilation.MethodsThis was a prospective observational study in critically ill and mechanically ventilated patients, admitted to the medical intensive care unit of a university hospital. Nineteen measurements were made in a total of 10 patients at various intervals after starting mechanical ventilation. In seven patients, measurements were made on two or more occasions, with a minimum interval of 24 hours.ResultsThe TwPdi was 11.5 ± 3.9 cm H2O (mean ± SD), indicating severe respiratory muscle weakness. The between-occasion coefficient of variation of TwPdi was 9.7%, comparable with data from healthy volunteers. Increasing duration of mechanical ventilation was associated with a logarithmic decline in TwPdi (R = 0.69; P = 0.038). This association was also found for cumulative time on pressure control (R = 0.71; P = 0.03) and pressure-support ventilation (P = 0.05; R = 0.66) separately, as well as for cumulative dose of propofol (R = 0.66; P = 0.05) and piritramide (R = 0.79; P = 0.01).ConclusionsDuration of mechanical ventilation is associated with a logarithmic decline in diaphragmatic force, which is compatible with the concept of VIDD. The observed decline may also be due to other potentially contributing factors such as sedatives/analgesics, sepsis, or others.

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).

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

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.

Clinical review: intensive care unit acquired weakness.

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).

Interobserver agreement of medical research council sum-score and handgrip strength in the intensive care unit

A substantial number of patients admitted to the ICU because of an acute illness, complicated surgery, severe trauma, or burn injury will develop a de novo form of muscle weakness during the ICU stay that is referred to as “intensive care unit acquired weakness” (ICUAW). This ICUAW evoked by critical illness can be due to axonal neuropathy, primary myopathy, or both. Underlying pathophysiological mechanisms comprise microvascular, electrical, metabolic, and bioenergetic alterations, interacting in a complex way and culminating in loss of muscle strength and/or muscle atrophy. ICUAW is typically symmetrical and affects predominantly proximal limb muscles and respiratory muscles, whereas facial and ocular muscles are often spared. The main risk factors for ICUAW include high severity of illness upon admission, sepsis, multiple organ failure, prolonged immobilization, and hyperglycemia, and also older patients have a higher risk. The role of corticosteroids and neuromuscular blocking agents remains unclear. ICUAW is diagnosed in awake and cooperative patients by bedside manual testing of muscle strength and the severity is scored by the Medical Research Council sum score. In cases of atypical clinical presentation or evolution, additional electrophysiological testing may be required for differential diagnosis. The cornerstones of prevention are aggressive treatment of sepsis, early mobilization, preventing hyperglycemia with insulin, and avoiding the use parenteral nutrition during the first week of critical illness. Weak patients clearly have worse acute outcomes and consume more healthcare resources. Recovery usually occurs within weeks or months, although it may be incomplete with weakness persisting up to 2 years after ICU discharge. Prognosis appears compromised when the cause of ICUAW involves critical illness polyneuropathy, whereas isolated critical illness myopathy may have a better prognosis. In addition, ICUAW has shown to contribute to the risk of 1-year mortality. Future research should focus on new preventive and/or therapeutic strategies for this detrimental complication of critical illness and on clarifying how ICUAW contributes to poor longer-term prognosis.

Muscle atrophy and preferential loss of myosin in prolonged critically ill patients

Introduction: Muscle weakness often complicates critical illness and is associated with devastating short‐ and long‐term consequences. For interventional studies, reliable measurements of muscle force in the intensive care unit (ICU) are needed. Methods: To examine interobserver agreement, two observers independently measured Medical Research Council (MRC) sum‐score (n = 75) and handgrip strength (n = 46) in a cross‐sectional ICU sample. Results: The intraclass correlation coefficient (ICC) for MRC sum‐score was 0.95 (0.92–0.97). The kappa coefficient for identifying “significant weakness” (MRC sum‐score <48, MRC subtotal upper limbs <24) and “severe weakness” (MRC sum‐score <36) was 0.68 ± 0.09, 0.88 ± 0.07, and 0.93 ± 0.07, respectively. The ICC for left and right handgrip strength was 0.97 (0.94–0.98) and 0.93 (0.86–0.97), respectively. Conclusions: Interobserver agreement on MRC sum‐score and handgrip strength in the ICU was very good. Agreement on “severe weakness” (MRC sum‐score <36) was excellent and supports its use in interventional studies. Agreement on “significant weakness” (MRC sum‐score <48) was good, but even better using the equivalent cut‐off in the upper limbs. It remains to be determined whether this may serve as a substitute. Muscle Nerve 45: 18–25, 2012