Exploration of muscle loss and metabolic state during prolonged critical illness: Implications for intervention?

Autoři: Liesl Wandrag aff001;  Stephen J. Brett aff004;  Gary S. Frost aff001;  Vasiliki Bountziouka aff005;  Mary Hickson aff001
Působiště autorů: Section for Nutrition Research, Department of Metabolism, Digestion and Reproduction, Imperial College London, England, United Kingdom aff001;  Department of Nutrition and Dietetics, Guy’s and St Thomas’ NHS Foundation Trust, London, England, United Kingdom aff002;  Department of Critical Care, Guy’s and St Thomas’ NHS Foundation Trust, London, England, United Kingdom aff003;  Centre for Peri-operative Medicine and Critical Care Research, Imperial College Healthcare NHS Trust, London, England, United Kingdom aff004;  Statistical Support Service, Population, Policy and Practice Programme, Institute of Child Health, University College, London, United Kingdom aff005;  Institute of Health and Community, University of Plymouth, Devon, England, United Kingdom aff006
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224565



Muscle wasting in the critically ill is up to 2% per day and delays patient recovery and rehabilitation. It is linked to inflammation, organ failure and severity of illness. The aims of this study were to understand the relationship between muscle depth loss, and nutritional and inflammatory markers during prolonged critical illness. Secondly, to identify when during critical illness catabolism might decrease, such that targeted nutritional strategies may logically be initiated.


This study was conducted in adult intensive care units in two large teaching hospitals. Patients anticipated to be ventilated for >48 hours were included. Serum C-reactive protein (mg/L), urinary urea (mmol/24h), 3-methylhistidine (μmol/24h) and nitrogen balance (g/24h) were measured on days 1, 3, 7 and 14 of the study. Muscle depth (cm) on ultrasound were measured on the same days over the bicep (bicep and brachialis muscle), forearm (flexor compartment of muscle) and thigh (rectus femoris and vastus intermedius).


Seventy-eight critically ill patients were included with mean age of 59 years (SD: 16) and median Intensive care unit (ICU) length of stay of 10 days (IQR: 6–16). Starting muscle depth, 8.5cm (SD: 3.2) to end muscle depth, 6.8cm (SD: 2.2) were on average significantly different over 14 days, with mean difference -1.67cm (95%CI: -2.3 to -1cm), p<0.0001. Protein breakdown and inflammation continued over 14 days of the study.


Our patients demonstrated a continuous muscle depth loss and negative nitrogen balance over the 14 days of the study. Catabolism remained dominant throughout the study period. No obvious ‘nutritional tipping point” to identify anabolism or recovery could be identified in our cohort. Our ICU patient cohort is one with a moderately prolonged stay. This group showed little consistency in data, reflecting the individuality of both disease and response. The data are consistent with a conclusion that a time based assumption of a tipping point does not exist.

Trial registration

International Standard Randomised Controlled Trial Number: ISRCTN79066838. Registration 25 July 2012.

Klíčová slova:

Balance and falls – Inflammation – Intensive care units – Muscle analysis – Muscle proteins – Urea – Catabolism


1. NICE 2. Rehabilitation after critical illness (CG83). 4-10-2009. Online Source.

2. Bear DE, Wandrag L, Merriweather JL, Connolly B, Hart N, Grocott MPW and on behalf of the Enhanced Recovery After Critical Illness Programme Group (ERACIP) investigators. The role of nutritional support in the physical and functional recovery of critically ill patients: a narrative review. Critical Care (2017) 21:226. doi: 10.1186/s13054-017-1810-2 28841893

3. Herridge MS, Cheung AM, Tansey CM, Matte-Martyn A, Diaz-Granados N, Al Saidi F, et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003 Feb 20;348(8):683–93. doi: 10.1056/NEJMoa022450 12594312

4. Herridge MS. The challenge of designing a post-critical illness rehabilitation intervention. Crit Care 2011 Oct 25;15(5):1002. doi: 10.1186/cc10362 22047913

5. Chan KS., Mourtzakis M, Friedman L, Dinglas VD, Hough CL, Wesley E, et l. Acute Respiratory Distress Syndrome (ARDS) Network. Evaluating Muscle Mass in Survivors of Acute Respiratory Distress Syndrome: A 1-Year Multicenter Longitudinal Study, Crit Care Med 2018.

6. Klaude M, Fredriksson K, Tjader I, Hammarqvist F, Ahlman B, Rooyackers O, et al. Proteasome proteolytic activity in skeletal muscle is increased in patients with sepsis. Clin Sci (Lond) 2007 Jul;112(9):499–506.

7. Puthucheary ZA, Rawal J, McPhail M, Connolly B, Ratnayake G, Chan P, et al. Acute skeletal muscle wasting in critical illness. JAMA 2013 Oct 16;310(15):1591–600. doi: 10.1001/jama.2013.278481 24108501

8. Wandrag L, Siervo M, Riley HL, Khosravi M, Fernandez BO, Leckstrom CA, et al, for the Caudwell Xtreme Everest Research Group. Does hypoxia play a role in the development of sarcopenia in humans? Mechanistic insights from the Caudwell Xtreme Everest Expedition. Redox Biology 13 (2017) 60–68. doi: 10.1016/j.redox.2017.05.004 28570949

9. Frost RA, Lang CH. Skeletal muscle cytokines: regulation by pathogen-associated molecules and catabolic hormones. Curr Opin Clin Nutr Metab Care 2005 May;8(3):255–63. 15809527

10. Winkelman C. Inactivity and inflammation: selected cytokines as biologic mediators in muscle dysfunction during critical illness. AACN Clin Issues 2004 Jan;15(1):74–82. 14767366

11. Hasselgren PO, Alamdari N, Aversa Z, Gonnella P, Smith IJ, Tizio S. Corticosteroids and muscle wasting: role of transcription factors, nuclear cofactors, and hyperacetylation. Curr Opin Clin Nutr Metab Care 2010 Jul;13(4):423–8. doi: 10.1097/MCO.0b013e32833a5107 20473154

12. Gamrin-Gripenberg L, Sundström-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. Critical Care 2018 Jan 23;22(1):13. doi: 10.1186/s13054-017-1932-6 29361961

13. Reid CL, Campbell IT, Little RA. Muscle wasting and energy balance in critical illness. Clin Nutr 2004 Apr;23(2):273–80. doi: 10.1016/S0261-5614(03)00129-8 15030968

14. Weijs PJM, Looijaard WG, Beishuizen A, Girbes ARJ, Oudemans-van Straaten HM. Early high protein intake is associated with low mortality and energy overfeeding with high mortality in non-septic mechanically ventilated critically ill patients. Critical Care201418:701 doi: 10.1186/s13054-014-0701-z 25499096

15. Looijaard WG, Dekker IM, Stapel SN, Girbes AR, Twisk JW, OUdemans-van Straaten HM, et al. Skeletal muscle quality as assessed by CT-derived skeletal muscle density is associated with 6-month mortality in mechanically ventilated critically ill patients. Crit Care2016 Dec 1;20(1):386. doi: 10.1186/s13054-016-1563-3 27903267

16. Arabi YM, Casaer MP, Chapman M, Heyland DK, Ichai C, Marik PE,et al. The intensive care medicine research agenda in nutrition and metabolism. Intensive Care Med 2017 Sep;43(9):1239–1256. doi: 10.1007/s00134-017-4711-6 28374096

17. Fraipont V, Preiser JC. Energy estimation and measurement in critically ill patients. JPEN J Parenter Enteral Nutr 2013 Nov;37(6):705–13. doi: 10.1177/0148607113505868 24113283

18. A Pocket Guide to Clinical Nutrition, 4th Edition, Parenteral and Enteral Nutrition Group of the British Dietetic Association, 2011. ISBN 978-0-9529869-2-8.

19. Deacon A, Sherwood RA, Hooper J, Association for Clinical Biochemistry (Great Britain). Calculations in laboratory science. ACB Venture Publications; 2009.

20. Frankenfield D, Smith JS, Cooney RN. Validation of 2 approaches to predicting resting metabolic rate in critically ill patients. JPEN J Parenter Enteral Nutr 2004 Jul;28(4):259–64. doi: 10.1177/0148607104028004259 15291408

21. Singer P, Reintam Blaser A, Berger MM, Alhazzani W, Calder PC, Casaer M, et al. ESPEN guideline on clinical nutrition in the intensive care unit, Clinical Nutrition (2018), https://doi.org/10.1016/j.clnu.2018.08.037.

22. McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, et al; Society of Critical Care Medicine; American Society for Parenteral and Enteral Nutrition. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN 2016 Feb;40(2):159–211.

23. Iwashyna TJ, Hodgson CL, Pilcher D, Bailey M, van Lint A, Chavan S, 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: 566–73. doi: 10.1016/S2213-2600(16)30098-4 27155770

24. Liebau F, Wernerman J, van Loon LJ, Rooyackers O. Effect of initiating enteral protein feeding on whole-body protein turnover in critically ill patients. Am J Clin Nutr 2015 Mar;101(3):549–57. doi: 10.3945/ajcn.114.091934 25733640

25. Plank LD. Protein for the critically ill patient-what and when? Eur J Clin Nutr 2013 Feb 13.

26. Preiser JC, V Zanter ARH, Berger MM, Biolo G, Casaer MP, Doig GS, et al. Metabolic and nutritional support of critically ill patients: consencus and controversies. Critical Care (2015) 19:35. doi: 10.1186/s13054-015-0737-8 25886997

27. Biolo G, Maggi SP, Williams BD, Tipton KD, Wolfe RR. Increased rates of muscle protein turnover and amino acid transport after resistance exercise in humans. Am J Physiol 1995 Mar;268(3 Pt 1):E514–E520. doi: 10.1152/ajpendo.1995.268.3.E514 7900797

28. Cermak NM, Res PT, de Groot LC, Saris WH, van Loon LJ. Protein supplementation augments the adaptive response of skeletal muscle to resistance-type exercise training: a meta-analysis. Am J Clin Nutr 2012 Dec;96(6):1454–64. doi: 10.3945/ajcn.112.037556 23134885

29. Churchward-Venne TA, Murphy CH, Longland TM, Phillips SM. Role of protein and amino acids in promoting lean mass accretion with resistance exercise and attenuating lean mass loss during energy deficit in humans. Amino Acids 2013 May 5.

30. Harvey SE, Parrott F, Harrison DA, Bear DE, Segaran E, Beale R, et al. Trial of the route of early nutritional support in critically ill adults. N Engl J Med 2014 Oct 30;371(18):1673–84. doi: 10.1056/NEJMoa1409860 25271389

31. Heyland DK, Cahill NE, Dhaliwal R, Sun X, Day AG, McClave SA. Impact of enteral feeding protocols on enteral nutrition delivery: results of a multicenter observational study. JPEN J Parenter Enteral Nutr 2010 Nov;34(6):675–84. doi: 10.1177/0148607110364843 21097768

32. Wandrag L, Gordon F, O'Flynn J, Siddiqui B, Hickson M. Identifying the factors that influence energy deficit in the adult intensive care unit: a mixed linear model analysis. J Hum Nutr Diet 2011 Feb 21.

33. Hasselgren PO. Catabolic response to stress and injury: implications for regulation. World J Surg 2000 Dec;24(12):1452–9. doi: 10.1007/s002680010262 11193708

34. Connolly B, MacBean V, Crowley C, Lunt A, Moxham J, Rafferty GF, et al. Ultrasound for the assessment of peripheral skeletal muscle architecture in critical illness: a systematic review. Crit Care Med 2015 Apr;43(4):897–905. doi: 10.1097/CCM.0000000000000821 25559437

35. Dickerson RN, Tidwell AC, Minard G, Croce MA, Brown RO. Predicting total urinary nitrogen excretion from urinary urea nitrogen excretion in multiple-trauma patients receiving specialized nutritional support. Nutrition 2005 Mar;21(3):332–8. doi: 10.1016/j.nut.2004.07.005 15797675

36. Chinkes DL. Methods for measuring tissue protein breakdown rate in vivo. Curr Opin Clin Nutr Metab Care 2005 Sep;8(5):534–7. 16079625

Článek vyšel v časopise


2019 Číslo 11