Kroppens reaktion ved faste og stress metabolisme DSKE temadag 23. Marts 2015

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1 Kroppens reaktion ved faste og stress metabolisme DSKE temadag 23. Marts 2015 Hvorfor vigtigt? Metabolisme dødsårsager ved faste og stress-metabolisme Proteinbehov anabol resistens aminosyre-behov Jens Kondrup. Overlæge, Ernæringsenheden, Rigshospitalet

2 Ernæringsterapi hos den stress-metabole patient Hungersnød underernæring; ernæringsterapi er kausal behandling Sygdomme dårlig almentilstand; komplikationer; dårlig livskvalitet. Underernæring er én af komplikationerne (stress-metabolisme nedsat appetit, øgede behov) Immobilisering Infektioner Dårlig sårheling etc Alle disse konsekvenser af underernæring kan have andre årsager Ernæringsterapi hjælper, hvis underernæring er en væsentlig (med-) årsag til tilstanden. Stress-metabolisme katabolisme kachexi metaboliske forstyrrelser ved inflammatoriske tilstande.

3 Starvation Disease Low intake Inflammatory metabolism Decreased requirements Increased requirements - Malnutrition Impaired function Complications according to primary condition

4 Konkurrerende årsager? andre apopleksi neurologi underernæring inaktivitet(fraktur) andre muskelatrofi gangbesvær Ernæringsterapi vil virke på gangbesvær, hvis underernæring er en dominerende årsag til gangbesværet, men i mindre grad hvis underernæringen er en mindre del af de samlede årsager til gangbesværet.

5 Protein requirement and utilization Malnourished (Barac-Nieto 1979) 0.75 Balance (g protein/kg per d) Recommendation Requirement Healthy (Norgan 1980) Multiple fractures Burns (Larsson 1990) Intake (g protein/kg per d) Kondrup J, Nielsen K. Z Gastroenterol 1996;34:26-31.

6 In the hospital: malnutrition & clinical condition, i.e. nutritional status and severity of disease (i.e. nutritional requirements/stress-metabolism) None 100 Degree of nutritional impairment of function Mild Moderate Severe Severity of disease Moderate Mild Severe Time Nutritional risk = risk of complications due to nutritional impairment

7 Energidepoter ved 1800 Kcal per dag Kilde Væv Kg Kcal Varighed Fedt Fedtvæv Protein Muskel 6 1) Glykogen Muskel 0, ,3 Lever 0, ,15 I alt ) Kun ca. ½ af total 12 kg er mobiliserbar

8 Kroppens reaktion ved faste og stress metabolisme DSKE temadag 23. Marts 2015 Hvorfor vigtigt? Metabolisme dødsårsager ved faste og stress-metabolisme Proteinbehov anabol resistens aminosyre-behov Jens Kondrup. Overlæge, Ernæringsenheden, Rigshospitalet

9 Death predictors in sepsis in 25 ICU patients Moyer et al. 1981; J Trauma 21: non-survivors survivors non-survivors survivors non-survivors survivors non-survivors survivors non-survivors survivors non-survivors survivors non-survivors survivors non-survivors survivors non-survivors survivors non-survivors survivors non-survivors Prediction of mortality: Urea Non-ess AA 0.71 Orosomucoid Lactate BCAA 0.64 Glutamin 0.67 pa-o NS: ph, CO 2, HR, BP, RF Glucose Lactate FFA OHBut AA Urea ammonia insulin glucagon cortisol orosomucoid survivors mm

10 Splanchnic metabolism in non-sepsis SIRS, sepsis and multiorgan failure Wilmore et al. Ann Surg 1980; 192: Ctr SIRS Sepsis MOF % burn Cardiac index, l/min per m O 2 uptake, ml/min per m Glucose, mm Spl O 2 uptake, ml/min per m Spl glucose output, mmol/min per m P-lactate, mm spl lactate uptake, mmol/min per m P-alanine, mm spl alanine uptake, mmol/min per m P-C reactive protein, mg/dl <

11 Metabolism of wound Wilmore et al. Ann Surg 1977; 186: Ctr small large % burn % leg burn Glucoce mm Cardiac index, l/min per m O 2 uptake, ml/min per m Leg blood flow, ml/min per 100 ml Leg O 2 uptake, ml/min per m Leg glucose uptake, mg/min per 100 ml Leg lactate release, mg/min per 100 ml Leg venous O 2, ml/100 ml

12 24 t faste 1800 kcal/day Adipose tissue 130 g FFA 90 g FFA 40 g FFA 50 g KB Muscle 75 g AA Faste 30 g Loss of tissue (muscle, skin, intestine) Loss of nitrogen Ery Immune cells CO2 Liver 30 g glykogen 130 g glucose Wound healing (fibroblasts, endothelium) Urea 12 g N 75 g AA 30 g lactate 100 g CNS 10 g ketonstoffer (KB) Bursztein et al 1991; Cahill et al weeks' starvation 1450 kcal/day Adipose tissue Muscle Loss of tissue (muscle, skin, intestine) Loss of nitrogen 150 g FFA 80 g FFA 70 g FFA 30 g KB 20 g AA 30 g Ery Immune cells CO2 Liver 80 g glucose Wound healing (fibroblasts, endothelium) Urea 4 g N 50 g 25 g AA 1) 50 g lactate CNS 1) less without acidosis 60 g ketonstoffer (KB) Bursztein et al 1991; Cahill et al

13 Adipose tissue 130 g FFA 90 g FFA 40 g FFA 50 g KB Muscle 24 t faste 1800 kcal/day Traume 75 g AA 30 g Loss of tissue (muscle, skin, intestine) Loss of nitrogen Ery Immune cells CO2 Liver 30 g glykogen 130 g glucose Wound healing (fibroblasts, endothelium) Urea 12 g N 75 g AA 30 g lactate 100 g CNS 10 g ketonstoffer (KB) Bursztein et al 1991; Cahill et al t faste + traume (brandsår) 2700 kcal/day Adipose tissue Muscle Loss of tissue (muscle, skin, intestine) Loss of nitrogen 200 g FFA 180 g FFA 20 g FFA 30 g KB Liver 50 g AA 130 g AA 40 g 370 g glucose 230 g Ery Immune cells Wound healing (fibroblasts, endothelium) CO2 Urea 30 g N 180 g AA 1) 230 g lactate 100 g CNS 1) more with acidosis 0 g ketonstoffer (KB) Bursztein et al 1991; Cahill et al

14 Starvation (S) versus Stress-metabolism (SM) S SM Cancer 24 h urinary nitrogen (LBM loss) REE P-glucose P-lactate P-FFA P-Ketone bodies P-Insulin Insulin resistance Glucose intolerance P-Catecholamines? P-Glucagon? P-Cortisol? P-TNF-α, Il-1, Il-6 Afferent nerves (pain)

15 Starvation CNS glucose Liver Muscle ketone bodies - amino acids free fatty acids Adipose tissue - : inhibits

16 Macronutrient regulation in stress metabolism (burns) CNS glucose lactate + Liver ketone bodies Muscle - Immune cells: macrophages etc Repair cells fibroblasts, endothelial cells) amino acids + - urinary nitrogen + free fatty acids Adipose Tissue After Bursztein et al 1991, and others : stimulates + - : inhibits

17 Katabole hormoner Hormon Årsag Effekt Katekolaminer Sympatikus (smerter) Feber, REE glykogenolyse glukoneogenese insulin-insensitivitet glukagon laktatproduktion (Na + /K + ATPase ) lipolyse Glukagon Katekolaminer glykogenolyse glukoneogenese ketogenese hepatisk AA optag, ureagenese, Cortisol Sympatikus (smerter) Katekolaminer TNF-α glukoneogenese insulin-insensitivitet lipolyse proteolyse

18 Stress metabolisme: Cytokiner Cytokin Årsag Effekt TNF-α, Il-1 Il-6 Aktivering af makrofag/monocyt Aktivering af makrofag/monocyt PG Feber, REE, Neuropeptid Y appetit ACTH cortisol proteolyse (direkte?) hepatisk AA optag GH receptor IGF-1 lipolyse ketogenese hepatisk AA optag proteolyse glukoneogenese ketogenese akut fase proteiner GH receptor IGF-1

19 Metabolism to recover Antigen/endotoxin/necrosis/tumor cells Complement + - Immune cells macrophages/endothelial cells - TNF- Il-1 Alpha-1 acid glycoprotein C-reactive protein Fibrinogen a 1 -antichymotrypsin Coeruloplasmin a 2 -macroglobulin Glutathion TNF- Il-1 Il-6 TNF- Il-1 Il-6 ROS PG, Tx, LT Histamine Glucocorticoids ACTH Liver IGF-I Muscle CNS - - Serotonine Neuropeptide Y Alanine, Glutamine, other AA Glucose Arginine Regeneration fibroblasts, endothelial cells - + = inhibits; = stimulates

20 Hunger: Død ved tab af: IRA fanger: ca. 40% vægt ca. 50% protein ca. 85% fedt øvrigt: ca. 50% LBM eller protein BMI <11-13 Leiter et al JAMA 248: Dødsårsager: respirationsstop pneumoni hudinfektioner diaré (dehydrering)

21 Varighed af faste Faste Stress 24 t 5-6 uger Brandsår REE, Kcal Fedt, g/d Protein, g/d Død ved tab af: 85% fedt (af 15 kg), dage % prot (af 12 kg), dage

22 Granulocyt: Sepsis: dødelighed relateret til fagocytose, O 2 -, TNF-α induceret adhærence Monocyt: HLA-DR, TNF-α receptor, TNF-α induceret cytokin produktion, LPS induceret Il-1 produktion Anergi (CD 4 Th1 celle: TNF-α ) Lavt akut fase protein response Autopsi: Tab af CD 4 T celler fra milt, tab af lymfocytter og epitelceller fra tarm (apoptose, ikke nekrose). Mitokondrie dysfunktion og apoptose i monocytter Andre us.: Høj plasma TNF-α, Il-1, Il-6, Il-10 - men ingen større histologisk påvirkning af svigtende organer (ingen nekrose) celler holder bare op : stunning Hotchkiss et al N Eng J Med 2003; 348: Adrie et al 2001; Am J Respir Crit care Med 164; Adrie Int Care Med 2000; 26: Calvano et al. Arch Surg 1998; 133:

23 Kroppens reaktion ved faste og stress metabolisme DSKE temadag 23. Marts 2015 Hvorfor vigtigt? Metabolisme dødsårsager ved faste og stress-metabolisme Proteinbehov anabol resistens aminosyre-behov Jens Kondrup. Overlæge, Ernæringsenheden, Rigshospitalet

24 Duke et al. Surgery 1970; 68: Pre-op Post-op Sepsis Trauma Burns Protein Energy % P E % P E % P E % P E % P E % Hvis kcal/kg 18 E%= g/kg per dag

25 Repletion Protein balance (g/kg per dag) Shaw 83 Rudman 75 Barac-Nieto 79 Cirrhose Raske (Norgan 1980) protein indtag (g/kg per dag)

26 Protein utilization in cancer patients Bennegard et al Gastroenterology 85: Balance (g protein/kg per d) GI Cancer GI benign Protein intake (g protein/kg per d)

27 Protein requirement after major GI surgery Moghissi 77 Sagar Freund 79 Jensen 85 Balance (g protein/kg per d) Moore 86 Figueras 88 Woolfson 89 Hansell 89 Hw ang 93 Sandström 93 Beier-H 96 Singh 98 Moore 92 Daly 84 Bow er 86 Lim 81 Hoover 80 Stehle 89 gln Hammarquist 90 gln Protein intake (g protein/kg per d) Morlion 98 gln

28 Protein requirement after major GI surgery All ptt received 1.5 g protein/kg per day PN Tashiro et al. Nutrition 1996;12: Preop esophagus resection gastric/colon resection 0.5 Balance (g protein/kg per d) Postop D10 Postop D3 Postop D10 Postop D h urinary catecholamines (µg/kg per d)

29 Protein requirement in ICU patients 0.5 Balance (g protein/kg per d) Cerra 86 (sepsis, surg) Larsson 90 (burns, trauma) Pitkänen 91(sepsis, trauma) Grahm 89 (head) Clifton (head) Macias 96 (ATIN, CVVH) 2042jk 92 (ICU) Protein intake (g protein/kg per d)

30 E/N ratio Kreymann et al. Clin Nutr 2012, 31: E% protein 18 E% protein 26 E% protein E% protein = 2560/(E/N ratio)

31 Protein intake, N excretion and N balance at given intakes Based on Kreymann et al. Clin Nutr 2012, 31: g protein/kg per day Severity of Disease Diagnosis P intake P excretion P balance 0 (N=28) 1 (N=14) 2 (N=12) 3 (=32) Healthy Malnourished Alcoholics Obese Post-obese HIV infection Crohn s Colitis Femoral fracture Emphysema Cancer Spinal injury Sepsis GI Surgery Stroke Critically ill Trauma Head injury Burns

32 Balance (g protein/kg per d) Ved indtag = ca. 1 g/kg er patienter med sværhedsgrad i sygdom score i mere negativ balance end de raske og ikke-syge med score = 0. Proteinbehovet kan skønnes at være indtaget + den negative balance, d.v.s. ca. 1,3 g/kg for score = 1 og ca. 1,7 g/kg for score = 2. Patienter med score = 3 fik lidt mere protein, men var næsten i samme negative balance som patienter med score = 2, d.v.s. endnu højere behov. For disse patienter skal det dog dokumenteres, at de kan udnytte en højere proteinindgift, f.eks. ved måling af du-carbamid.

33 EFFECTS OF AMINO ACID INFUSION ON SKELETAL MUSCLE PROTEIN BALANCE IN SEVERELY BURNED PATIENTS Biolo & Wolfe, Clinical Nutrition (abstract) 2001 MUSCLE PROTEIN BALANCE phenylalanine nmol/min/100 ml Healthy volunteers * Burned patients # *# Postabsorptive state Amino acid infusion *, P<0.05 vs. postabsorptive state #, P<0.05 vs. healthy volunteers

34 Kroppens reaktion ved faste og stress metabolisme DSKE temadag 23. Marts 2015 Hvorfor vigtigt? Metabolisme dødsårsager ved faste og stress-metabolisme Proteinbehov anabol resistens aminosyre-behov Jens Kondrup. Overlæge, Ernæringsenheden, Rigshospitalet

35 Protein requirement and utilization Malnourished (Barac-Nieto 1979) 0.75 Balance (g protein/kg per d) Recommendation Requirement Healthy (Norgan 1980) Multiple fractures Burns (Larsson 1990) Intake (g protein/kg per d) - fordi vi giver de forkerte aminosyrer? Kondrup J, Nielsen K. Z Gastroenterol 1996;34:26-31.

36 asp asn pro cys met phe arg orn cit tau total AA sum BCAA lys his trp tyr leu ile val ala gly gln glu ser thr Percent of control values

37 asp asn pro phe arg orn cit tau total AA sum BCAA lys his trp met ile leu tyr gly ala val cys gln glu ser thr After/before hip surg After/before abd surg AA in surgery Percent of controls, or before values

38 asp asn pro cys met phe lys arg orn cit tau total AA sum BCAA his trp tyr leu ile val ala gly gln glu ser thr Percent of controls, or before values

39 Protein requirement after major GI surgery Moghissi 77 Sagar Freund 79 Jensen 85 Balance (g protein/kg per d) Moore 86 Figueras 88 Woolfson 89 Hansell 89 Hw ang 93 Sandström 93 Beier-H 96 Singh 98 Moore 92 Daly 84 Bow er 86 Lim 81 Hoover 80 Stehle 89 gln Hammarquist 90 gln Protein intake (g protein/kg per d) Morlion 98 gln

40 Kroppens reaktion ved faste og stress metabolisme Konklusioner Vigtigt for at forstå den mulige effekt af ernæringsterapi hos den enkelte patient Hvis metabolismen kunne behandles, ville almindelig mad være nok Proteinbehov: øget, men god nyttevirkning (anabol resistens er kompetitiv hæming) aminosyre-sammensætning svarende til vanlige anbefalinger?