Effect of Intermittent or Continuous Feed on Muscle Wasting in Critical Illness
2020; Elsevier BV; Volume: 158; Issue: 1 Linguagem: Inglês
10.1016/j.chest.2020.03.045
ISSN1931-3543
AutoresAngela McNelly, Danielle E. Bear, Bronwen Connolly, Gill Arbane, Laura Allum, Azhar Tarbhai, Jackie A. Cooper, Philip Hopkins, Matt P. Wise, David Brealey, Kieron Rooney, Jason Cupitt, Bryan Carr, Kiran V.K. Koelfat, Steven W.M. Olde Damink, Philip J. Atherton, Nicholas Hart, Hugh Montgomery, Zudin Puthucheary,
Tópico(s)Nutrition and Health in Aging
ResumoBackgroundAcute skeletal muscle wasting in critical illness is associated with excess morbidity and mortality. Continuous feeding may suppress muscle protein synthesis as a result of the muscle-full effect, unlike intermittent feeding, which may ameliorate it.Research QuestionDoes intermittent enteral feed decrease muscle wasting compared with continuous feed in critically ill patients?Study Design and MethodsIn a phase 2 interventional single-blinded randomized controlled trial, 121 mechanically ventilated adult patients with multiorgan failure were recruited following prospective informed consultee assent. They were randomized to the intervention group (intermittent enteral feeding from six 4-hourly feeds per 24 h, n = 62) or control group (standard continuous enteral feeding, n = 59). The primary outcome was 10-day loss of rectus femoris muscle cross-sectional area determined by ultrasound. Secondary outcomes included nutritional target achievements, plasma amino acid concentrations, glycemic control, and physical function milestones.ResultsMuscle loss was similar between arms (–1.1% [95% CI, –6.1% to –4.0%]; P = .676). More intermittently fed patients received 80% or more of target protein (OR, 1.52 [1.16-1.99]; P < .001) and energy (OR, 1.59 [1.21-2.08]; P = .001). Plasma branched-chain amino acid concentrations before and after feeds were similar between arms on trial day 1 (71 μM [44-98 μM]; P = .547) and trial day 10 (239 μM [33-444 μM]; P = .178). During the 10-day intervention period the coefficient of variation for glucose concentrations was higher with intermittent feed (17.84 [18.6-20.4]) vs continuous feed (12.98 [14.0-15.7]; P < .001). However, days with reported hypoglycemia and insulin usage were similar in both groups. Safety profiles, gastric intolerance, physical function milestones, and discharge destinations did not differ between groups.InterpretationIntermittent feeding in early critical illness is not shown to preserve muscle mass in this trial despite resulting in a greater achievement of nutritional targets than continuous feeding. However, it is feasible and safe.Trial RegistryClinicalTrials.gov; No.: NCT02358512; URL: www.clinicaltrials.gov Acute skeletal muscle wasting in critical illness is associated with excess morbidity and mortality. Continuous feeding may suppress muscle protein synthesis as a result of the muscle-full effect, unlike intermittent feeding, which may ameliorate it. Does intermittent enteral feed decrease muscle wasting compared with continuous feed in critically ill patients? In a phase 2 interventional single-blinded randomized controlled trial, 121 mechanically ventilated adult patients with multiorgan failure were recruited following prospective informed consultee assent. They were randomized to the intervention group (intermittent enteral feeding from six 4-hourly feeds per 24 h, n = 62) or control group (standard continuous enteral feeding, n = 59). The primary outcome was 10-day loss of rectus femoris muscle cross-sectional area determined by ultrasound. Secondary outcomes included nutritional target achievements, plasma amino acid concentrations, glycemic control, and physical function milestones. Muscle loss was similar between arms (–1.1% [95% CI, –6.1% to –4.0%]; P = .676). More intermittently fed patients received 80% or more of target protein (OR, 1.52 [1.16-1.99]; P < .001) and energy (OR, 1.59 [1.21-2.08]; P = .001). Plasma branched-chain amino acid concentrations before and after feeds were similar between arms on trial day 1 (71 μM [44-98 μM]; P = .547) and trial day 10 (239 μM [33-444 μM]; P = .178). During the 10-day intervention period the coefficient of variation for glucose concentrations was higher with intermittent feed (17.84 [18.6-20.4]) vs continuous feed (12.98 [14.0-15.7]; P < .001). However, days with reported hypoglycemia and insulin usage were similar in both groups. Safety profiles, gastric intolerance, physical function milestones, and discharge destinations did not differ between groups. Intermittent feeding in early critical illness is not shown to preserve muscle mass in this trial despite resulting in a greater achievement of nutritional targets than continuous feeding. However, it is feasible and safe. ClinicalTrials.gov; No.: NCT02358512; URL: www.clinicaltrials.gov FOR EDITORIAL COMMENT, SEE PAGE 15Acute skeletal muscle wasting occurs rapidly in critical illness, and contributes to increases in length of stay, mortality, and functional disability.1Puthucheary Z.A. Rawal J. McPhail M. et al.Acute skeletal muscle wasting in critical illness.JAMA. 2013; 310: 1591-1600Crossref PubMed Scopus (1077) Google Scholar, 2Herridge M.S. Cheung A.M. Tansey C.M. et al.One-year outcomes in survivors of the acute respiratory distress syndrome.N Engl J Med. 2003; 348: 683-693Crossref PubMed Scopus (1667) Google Scholar, 3Ali N.A. O'Brien Jr., J.M. Hoffmann S.P. et al.Acquired weakness, handgrip strength, and mortality in critically ill patients.Am J Respir Crit Care Med. 2008; 178: 261-268Crossref PubMed Scopus (483) Google Scholar, 4Dinglas V.D. Aronson Friedman L. Colantuoni E. et al.Muscle weakness and 5-year survival in acute respiratory distress syndrome survivors.Crit Care Med. 2017; 45: 446-453Crossref PubMed Scopus (92) Google Scholar This in turn has significant detrimental impacts on patients, carers, and health service use postdischarge. This disability has proven resistant to exercise rehabilitation5Denehy L. Skinner E.H. Edbrooke L. et al.Exercise rehabilitation for patients with critical illness: a randomized controlled trial with 12 months of follow-up.Crit Care. 2013; 17: R156Crossref PubMed Scopus (266) Google Scholar, 6Morris P.E. Berry M.J. Files D.C. et al.Standardized rehabilitation and hospital length of stay among patients with acute respiratory failure: a randomized clinical trial.JAMA. 2016; 315: 2694-2702Crossref PubMed Scopus (214) Google Scholar, 7Walsh T.S. Salisbury L.G. Merriweather J.L. et al.Increased hospital-based physical rehabilitation and information provision after intensive care unit discharge: the RECOVER randomized clinical trial.JAMA Intern Med. 2015; 175: 901-910Crossref PubMed Scopus (195) Google Scholar, 8Moss M. Nordon-Craft A. Malone D. et al.A randomized trial of an intensive physical therapy program for patients with acute respiratory failure.Am J Respir Crit Care Med. 2016; 193: 1101-1110Crossref PubMed Scopus (196) Google Scholar or goal-directed nutrition9Allingstrup M.J. Kondrup J. Wiis J. et al.Early goal-directed nutrition versus standard of care in adult intensive care patients: the single-centre, randomized, outcome assessor-blinded EAT-ICU trial.Intensive Care Med. 2017; 43: 1637-1647Crossref PubMed Scopus (153) Google Scholar interventions, highlighting the need for primary prevention. FOR EDITORIAL COMMENT, SEE PAGE 15 Decreased muscle protein synthesis is a major pathophysiologic component of muscle wasting,1Puthucheary Z.A. Rawal J. McPhail M. et al.Acute skeletal muscle wasting in critical illness.JAMA. 2013; 310: 1591-1600Crossref PubMed Scopus (1077) Google Scholar,10Gamrin-Gripenberg L. Sundstrom-Rehal M. Olsson D. Grip J. Wernerman J. Rooyackers O. An attenuated rate of leg muscle protein depletion and leg free amino acid efflux over time is seen in ICU long-stayers.Crit Care. 2018; 22: 13Crossref PubMed Scopus (32) Google Scholar and continuous feeding (CF) may contribute to this. Continuous provision (and continuously raised concentrations) of amino acids suppresses myofibrillar protein synthesis (the muscle-full effect11Millward D.J. Pacy P.J. Postprandial protein utilization and protein quality assessment in man.Clin Sci (Lond). 1995; 88: 597-606Crossref PubMed Scopus (48) Google Scholar), demonstrated in both enteral12Atherton P.J. Etheridge T. Watt P.W. et al.Muscle full effect after oral protein: time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling.Am J Clin Nutr. 2010; 92: 1080-1088Crossref PubMed Scopus (277) Google Scholar and parenteral amino acid delivery.13Bohé J. Low J.F.A. Wolfe R.R. Rennie M.J. Latency and duration of stimulation of human muscle protein synthesis during continuous infusion of amino acids.J Physiol (Lond). 2001; 532: 575-579Crossref Scopus (319) Google Scholar Conversely, peaks in amino acid concentration (leucine in particular14Wilkinson D.J. Bukhari S.S.I. Phillips B.E. et al.Effects of leucine-enriched essential amino acid and whey protein bolus dosing upon skeletal muscle protein synthesis at rest and after exercise in older women.Clin Nutr. 2018; 37: 2011-2021Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar) promote anabolism,15Phillips S.M. Glover E.I. Rennie M.J. Alterations of protein turnover underlying disuse atrophy in human skeletal muscle.J Appl Physiol. 2009; 107: 645-654Crossref PubMed Scopus (211) Google Scholar and intermittent feeding of critically ill patients might therefore be advantageous. Intermittent feeding (IF) increases splanchnic blood flow and results in pulsatile changes in ghrelin, insulin, and peptide YY concentrations,16Chowdhury A.H. Murray K. Hoad C.L. et al.Effects of bolus and continuous nasogastric feeding on gastric emptying, small bowel water content, superior mesenteric artery blood flow, and plasma hormone concentrations in healthy adults: a randomized crossover study.Ann Surg. 2016; 263: 450-457Crossref PubMed Scopus (49) Google Scholar which may increase amino acid availability, further stimulating muscle protein synthesis. For these reasons, studying the benefits of IF in the critically ill has been strongly advocated17Arabi Y.M. Casaer M.P. Chapman M. et al.The intensive care medicine research agenda in nutrition and metabolism.Intensive Care Med. 2017; 43: 1239-1256Crossref PubMed Scopus (126) Google Scholar as this may offer a more efficacious form of acute nutrition support18Deutschman C.S. Ahrens T. Cairns C.B. Sessler C.N. Parsons P.E. Critical Care Societies Collaborative/USCIITG Task Force on Critical Care Research. Multisociety task force for critical care research: key issues and recommendations.Am J Respir Crit Care Med. 2012; 185: 96-102Crossref PubMed Scopus (19) Google Scholar and decrease the development of disability.19Batt J. dos Santos C.C. Cameron J.I. Herridge M.S. Intensive care unit–acquired weakness: clinical phenotypes and molecular mechanisms.Am J Respir Crit Care Med. 2013; 187: 238-246Crossref PubMed Scopus (158) Google Scholar We hypothesized that IF would abolish the muscle-full effect, and therefore ameliorate acute skeletal muscle wasting. This in turn may influence length of ICU/hospital stays, time on mechanical ventilation, Health-Related Quality of Life scores, functional ability, and gut-to-plasma amino acid transfer. The study was performed specifically in patients at risk of persistent critical illness, as these patients experience significant muscle wasting,1Puthucheary Z.A. Rawal J. McPhail M. et al.Acute skeletal muscle wasting in critical illness.JAMA. 2013; 310: 1591-1600Crossref PubMed Scopus (1077) Google Scholar are at greatest risk of subsequent functional disability, and are less likely to return home.20Iwashyna T.J. Hodgson C.L. Pilcher D. et al.Timing of onset and burden of persistent critical illness in Australia and New Zealand: a retrospective, population-based, observational study.Lancet Respir Med. 2016; 4: 566-573Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar,21Bagshaw S.M. Stelfox H.T. Iwashyna T.J. Bellomo R. Zuege D. Wang X. Timing of onset of persistent critical illness: a multi-centre retrospective cohort study.Intensive Care Med. 2018; 44: 2134-2144Crossref PubMed Scopus (42) Google Scholar This was a multicenter, single-blinded randomized controlled phase 2 trial conducted in eight mixed UK ICUs, with an allocation ratio of 1:1. Basic characteristics of the ICUs are shown in e-Table 1. Participants qualified for enrollment up to 24 h after ICU admission. Adult (> 18 years), expected to be intubated and ventilated for ≥ 48 h; requiring enteral nutrition via nasogastric tube; multiorgan failure (Sequential Organ Failure Assessment [SOFA] score22Vincent J. Moreno R. Takala J. et al.The SOFA (Sepsis-Related Organ Failure Assessment) score to describe organ dysfunction/failure: on behalf of the working group on sepsis-related problems of the European Society of Intensive Care Medicine.Intensive Care Med. 1996; 22: 707-710Crossref PubMed Scopus (7197) Google Scholar > 2 in ≥ 2 domains at admission); likely ICU stay ≥ 7 days and likely survival ≥ 10 days (assessed as previously by senior ICU clinicians1Puthucheary Z.A. Rawal J. McPhail M. et al.Acute skeletal muscle wasting in critical illness.JAMA. 2013; 310: 1591-1600Crossref PubMed Scopus (1077) Google Scholar). Prerandomization enteral feeding on the ward or > 12 h on ICU; unlikely to meet nutritional requirements by 72 h, using a standard feeding schedule (based on predicted clinical trajectory); need for sole/supplemental parenteral nutrition or postpyloric feeding on ICU admission. The full list of exclusions is available in e-Appendix 1. Prospective informed assent was obtained in writing from a nominated personal consultee or professional consultee. Retrospective participant consent was obtained on return of participant's mental capacity. Permission to use participants' data if capacity did not return or they did not survive was included in the assent process. The study received ethics committee approval (National Research Ethics Service Committee London-Queens Square; REC reference 14/LO/1792; IRAS project ID 160281) and was publicly registered before the first patient was randomized (ClinicalTrials.gov, NCT02358512). We used the CONSORT (Consolidated Standards of Reporting Trials) statement when reporting this trial.23von Elm E. Altman D.G. Egger M. et al.The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.J Clin Epidemiol. 2008; 61: 344-349Abstract Full Text Full Text PDF PubMed Scopus (5706) Google Scholar Enteral feeding was allowed for up to 6 h prerandomization. The same IF regimen (intervention) was used at every site, consisting of six 4-hourly feeds during 24 h,24Kadamani I. Itani M. Zahran E. Taha N. Incidence of aspiration and gastrointestinal complications in critically ill patients using continuous versus bolus infusion of enteral nutrition: a pseudo-randomised controlled trial.Aust Crit Care. 2014; 27: 188-193Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar administered via nasogastric tube using a syringe over 3 to 5 min. Depending on each Trust's approved supplier, either Ensure Compact (energy content, 2.4 kcal/mL; protein content, 0.104 g/mL; Abbott Nutrition) or Fortisip Compact Protein (energy content, 2.4 kcal/mL; protein content, 0.144 g/mL; Nutricia) was used, with a range of starter bolus sizes of 60 to 80 mL according to the participants' initial individual nutritional targets. The CF regimen (control) consisted of the total volume of feed administered over 24 h, as per local feeding protocols. The specific feed used for each patient in either arm of the trial was prescribed by each ICU's dietitian at a dose calculated to meet that patient's nutritional needs. Further details of the feeds and feeding protocols are described in the online article and in e-Table 2, and e-Figs 1 and 2. Nutrition targets were individualized by each unit's dietitian within 72 h of randomization. The modified Penn State equation or a weight-based equation (eg, 25 kcal/kg) was used to estimate energy targets. Protein targets were individualized with a minimum of 1.2 g/kg being used (actual body weight if BMI < 30 and ideal body weight if BMI > 30). After the intervention period, participants reverted to continuous feeding if enteral feed was required. Deviations from prescribed nutritional delivery (and their rationale) were recorded. The adequate nutritional threshold was set at > 80% of prescribed targets.25Heyland D.K. Cahill N. Day A.G. Optimal amount of calories for critically ill patients: depends on how you slice the cake!.Crit Care Med. 2011; 39: 2619-2626Crossref PubMed Scopus (204) Google Scholar Analysis was further performed on those achieving > 60%, in keeping with international practice.26Cahill N.E. Dhaliwal R. Day A.G. Jiang X. Heyland D.K. Nutrition therapy in the critical care setting: what is "best achievable" practice? An international multicenter observational study.Crit Care Med. 2010; 38: 395-401Crossref PubMed Scopus (311) Google Scholar The primary end point was change in rectus femoris cross-sectional area (RFCSA) on trial day 10.1Puthucheary Z.A. Rawal J. McPhail M. et al.Acute skeletal muscle wasting in critical illness.JAMA. 2013; 310: 1591-1600Crossref PubMed Scopus (1077) Google Scholar This method is fully validated for use in the critically ill,1Puthucheary Z.A. Rawal J. McPhail M. et al.Acute skeletal muscle wasting in critical illness.JAMA. 2013; 310: 1591-1600Crossref PubMed Scopus (1077) Google Scholar and was chosen as an outcome given the difficulties with volitional measures of physical function in acute critical illness.27Connolly B.A. Jones G.D. Curtis A.A. et al.Clinical predictive value of manual muscle strength testing during critical illness: an observational cohort study.Crit Care. 2013; 17: R229Crossref PubMed Scopus (78) Google Scholar Using B-mode ultrasound,1Puthucheary Z.A. Rawal J. McPhail M. et al.Acute skeletal muscle wasting in critical illness.JAMA. 2013; 310: 1591-1600Crossref PubMed Scopus (1077) Google Scholar RFCSA was measured on trial days 1, 7, and 10 after randomization and at ICU and hospital discharge. Members of the research team were trained to perform RFCSA measurements, and scan quality at each site was deemed adequate with an intraclass correlation coefficient > 0.9. Full details are provided in the online article. Secondary end points and their method of assessment are listed in Table 1. Blood samples were taken on trial days 1, 7, and 10. Plasma concentrations of 21 amino acids (including branched chain and nonbranched chain) were determined immediately before and 30 min after intermittent feeds at 9:00 and 13:00 in the intervention arm and at equivalent time points in the control arm. Plasma concentrations of citrulline (a marker of gut integrity28Piton G. Manzon C. Cypriani B. Carbonnel F. Capellier G. Acute intestinal failure in critically ill patients: is plasma citrulline the right marker?.Intensive Care Med. 2011; 37: 911-917Crossref PubMed Scopus (106) Google Scholar) were additionally measured.Table 1Secondary End Points and Methods of AssessmentSecondary End PointMethod of AssessmentPersonnelChange in muscle mass between trial day 7 and trial day 1Ultrasound-derived rectus femoris cross-sectional areaInvestigatorLength of ICU stayElectronic/paper clinical recordsInvestigatorLength of hospital stayElectronic/paper clinical recordsInvestigatorDays of mechanical ventilationElectronic/paper clinical recordsInvestigatorAmino acid concentrations (including citrulline)Biochemical analysis plasma samplesInvestigatorGastric residual volume (> 300 mL)Electronic/paper clinical recordsInvestigatorDiarrheaElectronic/paper clinical recordsInvestigatorVomitingElectronic/paper clinical recordsInvestigatorProkinetic useElectronic/paper clinical recordsInvestigatorDischarge locationElectronic/paper clinical recordsInvestigatorSit-to-stand test post-ICUBedside assessmentICU nurseBed-to-chair transfer post-ICUBedside assessmentICU nurse6-Minute Walk TestWard assessmentPhysiotherapistShort Physical Performance BatteryWard assessmentPhysiotherapistHealth-Related Quality of LifeWard assessment/SF-36 questionnaire (telephone)InvestigatorPrimary health care usage/costsElectronic medical recordsInvestigatorSF-36 = 36-Item Short Form Health Survey. Open table in a new tab SF-36 = 36-Item Short Form Health Survey. Measures of adverse safety impacts included proven or suspected aspiration, increased daily rates of vomiting or diarrhea (Bristol Stool Chart score ≥ 529Lewis S.J. Heaton K.W. Stool form scale as a useful guide to intestinal transit time.Scand J Gastroenterol. 1997; 32: 920-924Crossref PubMed Scopus (1911) Google Scholar), gastric residual volume (GRV) ≥ 300 mL, or impaired glycemic control from 4-hourly glucose measurements. Normoglycemia was defined as a blood glucose concentration of 4 to 10 mM, and thus concentrations of ≥ 10.1 or ≤ 3.9 mM were defined as hyperglycemia or hypoglycemia, respectively. Daily variation in blood glucose concentration was assessed by the coefficient of variation (SD/mean x 100).30Doola R. Greer R.M. Hurford R. et al.Glycaemic variability and its association with enteral and parenteral nutrition in critically ill ventilated patients.Clin Nutr. 2019; 38: 1707-1712Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Patients with multiorgan failure suffer a 21.5% (SD, 10.6) reduction of RFCSA in 10 days.1Puthucheary Z.A. Rawal J. McPhail M. et al.Acute skeletal muscle wasting in critical illness.JAMA. 2013; 310: 1591-1600Crossref PubMed Scopus (1077) Google Scholar A sample of 26 per group would give 90% power to detect a 10% difference between groups, at the 1% significance level. We performed a stratified analysis to allow for the different response of patients with preexisting chronic disease (defined as a stable chronic health condition requiring primary or secondary care follow-up),31Puthucheary Z.A. Denehy L. Exercise interventions in critical illness survivors: understanding inclusion and stratification criteria.Am J Respir Crit Care Med. 2015; 191: 1464-1467Crossref PubMed Scopus (41) Google Scholar,32McNelly A.S. Rawal J. Shrikrishna D. et al.An exploratory study of long-term outcome measures in critical illness survivors: construct validity of physical activity, frailty, and health-related quality of life measures.Crit Care Med. 2016; 44: e362-e369Crossref PubMed Scopus (33) Google Scholar estimating the proportion of chronic disease-to-nonchronic disease participants in the study cohort to be 2:1. A sample size of 29 per group would detect a large interaction effect (f = 0.4) for a factor with a 2:1 ratio of subgroups with 80% power at the 5% level.33Cohen J. Statistical Power Analysis for the Behavioral Sciences.2nd ed. Lawrence Erlbaum Associates, Mahwah, NJ1988Google Scholar Identifying those patients at risk of persistent critical illness is challenging, and a high dropout rate was expected from both early death and early recovery. We aimed to recruit at least 116 patients to allow for a dropout rate and protocol violations (common in many critical care trials) of up to 50%, with increased recruitment allowed to ensure equal numbers per arm. Randomization was stratified for recruitment site (1:1 basis), and for the presence of chronic disease, and occurred once assent was obtained. Treatment group allocation used an independent remote electronic web-based random allocation service to generate an unpredictable allocation outcome, and to conceal that outcome from research staff until assignment occurred. Z. A. P. (who assessed all ultrasound scans for the primary outcome) and the data analysts were blinded to allocation until data analysis was complete (see the online article). The statistical plan was designed by a statistician (J. A. C.), and approved a priori as part of the process of obtaining ethical approval. Further details are available in the online article. Both the intention-to-treat cohort and the per-protocol cohort (those that spent 10 days in ICU and had their muscle mass measured) were analyzed. We compared results between groups by analysis of variance with subgroup analysis by presence of chronic disease states. An adjustment for a small number of prespecified prognostic covariates (admission bicarbonate [HCO3−] and ratios of Pao2/Fio21Puthucheary Z.A. Rawal J. McPhail M. et al.Acute skeletal muscle wasting in critical illness.JAMA. 2013; 310: 1591-1600Crossref PubMed Scopus (1077) Google Scholar) was made by analysis of covariance. A change in RFCSA of –21.5% (as per power calculation) was assigned to those patients who were lost to follow-up or had their intervention discontinued9Allingstrup M.J. Kondrup J. Wiis J. et al.Early goal-directed nutrition versus standard of care in adult intensive care patients: the single-centre, randomized, outcome assessor-blinded EAT-ICU trial.Intensive Care Med. 2017; 43: 1637-1647Crossref PubMed Scopus (153) Google Scholar in the intention-to-treat analysis. Sensitivity analyses were performed with (1) a score assignment of –0% at 10 days, (2) multiple imputation, and (3) the per-protocol subgroup. All data were assessed for normality, using D'Agostino and Pearson omnibus normality tests. Data were then analyzed by Student t test, Pearson coefficient, Mann-Whitney U test, and Wilcoxon signed rank test as appropriate. The area under the curve was used as a measure of amino acid concentration.34Mitchell W.K. Phillips B.E. Hill I. et al.Human skeletal muscle is refractory to the anabolic effects of leucine during the postprandial muscle-full period in older men.Clin Sci (Lond). 2017; 131: 2643-2653Crossref PubMed Scopus (22) Google Scholar Glucose variability was described using the coefficient of variation.30Doola R. Greer R.M. Hurford R. et al.Glycaemic variability and its association with enteral and parenteral nutrition in critically ill ventilated patients.Clin Nutr. 2019; 38: 1707-1712Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Differences in nutritional delivery were assessed by Fisher exact test. Fragility indexes, describing the robustness or its lack ("fragility") of a clinical trial's results, were calculated. These indicate how many additional patients would be required in order for statistically significant results from a trial to be rendered nonsignificant.35Ridgeon E.E. Young P.J. Bellomo R. Mucchetti M. Lembo R. Landoni G. The fragility index in multicenter randomized controlled critical care trials.Crit Care Med. 2016; 44: 1278-1284Crossref PubMed Scopus (156) Google Scholar Two-tailed t tests were used, and statistical significance was indicated by P ≤ .05. Between February 9, 2015 and September 12, 2017, 3,487 patients were screened, of whom 2,926 were ineligible. Of these, 998 patients (29.7%) were not expected to be intubated for 24 h or more, 305 (9.1%) had single organ failure (SOFA score < 2 in two or more domains), and 307 (9.1%) were not expected to survive for 10 days. Of the 561 patients meeting inclusion criteria, 127 patients were randomized; 394 patients were unable to be recruited because of shortage of research staff, primarily outside the weekday recruitment period. Five were withdrawn before feed commenced and one was randomized in error, leaving 121 randomized: 62 in the intervention group and 59 in the control group. Ethical approval was given to increase recruitment so that randomization could continue until the minimum number per arm (determined a priori) was met (see the online article). A total of 63 patients completed the 10-day trial period (Fig 1); reasons for premature withdrawal are shown in e-Table 3. Participants' demographics were not different between trial arms (Table 2).Table 2Patient Characteristics and DemographicsCharacteristicAllIntermittent FeedingContinuous FeedingP Value(N = 121)(n = 62)(n = 59)Age, y57.7 (54.7-60.6)55.2 (51.0-59.3)60.3 (56.0-64.1).086Male, No. (%)aχ2 test was used.81 (66.9)41 (66.1)40 (67.8).997LOS before ICU admission, dbData represent median with range. Mann-Whitney U test was used.0.0 (0-15)0.0 (0-15)0.0 (0-15).259Period ventilated, dbData represent median with range. Mann-Whitney U test was used.7.3 (0.5-48)9.5 (0.5-48)6.0 (0.63-43).249ICU LOS, dbData represent median with range. Mann-Whitney U test was used.13.0 (0.7-93)13.0 (0.7-93)12.0 (1.5-52).626Hospital LOS, dbData represent median with range. Mann-Whitney U test was used.22.8 (1.5-183)22.0 (1.7-183)26.0 (1.5-102).907APACHE II score21.8 (19.9-23.6)23.1 (19.9-26.2)20.2 (18.2-22.3).134SOFA score on admission10.4 (9.7-11.0)10.3 (9.4-11.2)10.6 (9.6-11.5).709ICU survival, No. (%)aχ2 test was used.87.0 (71.9)44.0 (71.0)43.0 (72.9).173Hospital survival, No. (%)aχ2 test was used.79.0 (66.4)39.0 (63.9)40.0 (69.0).571RRT, No. (%)43.0 (36.8)25.0 (41.7)18.0 (31.6).338NMBA use, dbData represent median with range. Mann-Whitney U test was used.0.0 (0-9)1.0 (0-9)0.0 (0-7).109Hydrocortisone dose, mg,bData represent median with range. Mann-Whitney U test was used.,cCorticosteroid dosing as hydrocortisone equivalents. day 10.0 (0-800)0.0 (0-800)0.0 (0-800).240Hydrocortisone dose, mg, total by day 100.0 (0-25,000)0.0 (0-8,120)0.0 (0-25,000).149Statin use, No. (%)1 (0.01)0.0 (0)1.0 (0.02).495Gastroprotection, dbData represent median with range. Mann-Whitney U test was used.9.5 (0-11)10.0 (1-11)8.0 (0-11).569Vasopressor support, dbData represent median with range. Mann-Whitney U test was used.4.0 (0-22)4.0 (0-11)4.0 (0-22).962Sedation use, dbData represent median with range. Mann-Whitney U test was used.6.0 (0-11)7.0 (0-11)5.0 (0-11).279Total propofol dose, g, by day 1010.6 (3.9-10.6)11.3 (3.8-14.2)9.9 (3.6-9.9).377Admission diagnosis, No. (%) Sepsis47 (38.8)21 (33.9)26 (44.1) Cardiogenic shock27 (22.3)16 (25.8)11 (18.6) Trauma14 (11.6)6 (9.7)8 (13.6) Respiratory failure9 (7.4)6 (9.7)3 (5.1) Intracranial hemorrhage6 (5.0)3 (4.8)3 (5.1) Acute liver failure5 (4.1)2 (3.2)3 (5.1) Acute kidney Injury4 (3.3)3 (4.8)1 (1.7) Drug overdose4 (3.3)3 (4.8)1 (1.7) Emergency surgery3 (2.5)1 (1.6)2 (3.4) Cerebrovascular accident2 (1.7)1 (1.6)1 (1.7)Comorbidities, No. (%) Hypertension44 (36.4)24 (38.7)20 (33.9) Chronic respiratory diseases39
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