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Should we only think green? Update on hepatosplanchnic monitoring Alexander Wilmer, M.D., Ph.D.

Should we only think green? Update on hepatosplanchnic monitoring Alexander Wilmer, M.D., Ph.D. Medical Intensive Care University Hospital Gasthuisberg Catholic University of Leuven. Why hepatosplanchnic monitoring?.

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Should we only think green? Update on hepatosplanchnic monitoring Alexander Wilmer, M.D., Ph.D.

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  1. Should we only think green? Update on hepatosplanchnic monitoring Alexander Wilmer, M.D., Ph.D. Medical Intensive Care University Hospital Gasthuisberg Catholic University of Leuven

  2. Why hepatosplanchnic monitoring? Mostly, assessment of liver function in the ICU is based on “static” tests Tissue hypoxia within the GIT can occur under adequate global perfusion and oxygenation Dynamic liver function tests can reveal otherwise hidden hepatocellular dysfunction Loss of gut barrier function + bacterial translocation Conventional monitoring does not permit timely or differential detection of liver or GIT dysfunction and does not allow for monitoring of selective therapeutic targets

  3. 1) Techniques for monitoring of the GIT 2) Techniques for monitoring liver function Pubmed search, applicability for current ICU practice Evidence based criteria and experience based medicine No conflict of interests

  4. Techniques for monitoring of the GIT • Measurement of splanchnic blood flow (imaging techniques) • Gastrointestinal tonometry • Measurement of intestinal permeability • Biomarkers of intestinal enterocyte mass or function • Indocyanine green plasma disappearance rate

  5. Measurement of splanchnic blood flow with imaging techniques 1) Duplex Doppler ultrasound (DDUS) Useful for assessing thrombosis, flow patency before and after LTX + TIPS and for estimation of portal vein pressure. Inter- and intraobserver variability, imaging difficulties, outcome studies? 2) Mucosal laser Doppler flowmetery Assesses gastric mucosal perfusion, positioning? Experimental 3) MRI comparable to DDUS in the preoperative setting, less interobserver variability 4) Xenon-CT Total hepatic blood flow correlates well with Child-Pugh score and ICG disappearance Vermeulen M et al: Eur J Rad 2012, Takahashi H et al: Alcohol Clin Exp Res 2010, Sorbron S et al: Radiology 2012

  6. Gastrointestinal tonometry for measuring intestinal hypoperfusion Principle: Regional PCO2 = CO2 tissue production and removal => pHi (intramucosal) Pathophysiological assumption: Low pHi (↓ regional blood flow, DO2) is causally related to increased gut permeability Clinical studies: cause / effect relationship difficult to interpret together with lactate OK for prognosis Methodological problems: assumption of equal HCO3- in arterial blood + mucosa enteral feeding Time for CO2 equilibration Current applicability in the ICU for daily clinical practice: nihil

  7. Measurement of intestinal permeability Principle: urinary excretion of oligosaccharides after oral administration Pathophysiological assumption: Increased gut permeability facilitates MOF Clinical studies: increased permeability in burn, trauma, mixed critically ill patients Methodological problems: no ideal test at present: problems with either delivery, permeation, disposal or analysis Current applicability in the ICU: Permeability is increased: and now what? -> FXR agonists in the future?

  8. Measurement of biomarkers of enterocyte necrosis and GI dysfunction: citrulline (a nonessential AA) Synthesis: mainly from Glutamine (via glutamate tot ornithine) in mitochondria of enterocytes mainly in the small bowel Breakdown: 80% of citrulline produced is degraded to arginine in the kidney Reliable marker of enterocyte mass in chronic SB disease In critically ill patients: decreased, progressive decrease when in shock, related to intestinal dysfunction Low citrulline = marker of reduced enterocyte mass or of dysfunction Piton G et al: Int Care Med 2010 + 2011, Crenn P et al.: Clin Nutrition 2008, Luo M et al.: JPEN 2007, Luiking YC et al.: AM J Clin Nutr 2009 Oalled S et al.: Nutr Clin Pract. 2012

  9. Measurement of biomarkers of enterocyte necrosis and dysfunction: fatty acid binding protein Physiology: L-FABP and I-FABP: proteins used within enterocytes to deliver FA to specific metabolic sites, comprise about 4-6% of metabolic proteins Pathophysiology: Marker of enterocyte necrosis increased in SAP, intestinal infarction correlated with SB permeability and bacterial translocation In critically ill patients: If acutely reduced enterocyte mass: increased I-FABP If acute dysfunction: i-FABP expected to be normal Kanda T et al:. Gastroenterology 1996

  10. Grootjans J et al.: World J Gastroenterol 2010

  11. Techniques for monitoring of the GIT: usefulness for current ICU practice? • Measurement of splanchnic blood flow with imaging: DDUS yes • Gastrointestinal tonometry: no • Measurement of intestinal permeability: no • Biomarkers of intestinal enterocyte mass or function: yes (potential)

  12. Techniques for monitoring the liver: static tests • Static • Cholestasis • Hepatocellular integrity • Synthesis • Liver perfusion: CT, MRI

  13. Daily prevalence of liver dysfunction in the ICU Cholestasis = bili > 3 mg/dl or ALP > 400 + GGT > 80 IU/l % of patients Ischem hep = AST > 800 IU/l + ALT > 800 IU/l + PT < 70% Mixed = bili > 3 mg/dl + AST > 800 IU/l + + ALT > 800 IU/l + PT < 70% The Effect of Strict Blood Glucose Control on Biliary Sludge and Cholestasis in Critically Ill Patients. Dieter Mesotten, Joost Wauters, Greet Van den Berghe, Pieter J. Wouters, Ilse Milants, and Alexander Wilmer. J Clin Endocrinol Metab 2009; 2345-52. (n =658, 60% sepsis )

  14. Kortgen A at al.: Shock 2009

  15. Techniques for monitoring the liver: static versus dynamic tests • Dynamic • Elimination capacity: • Galactose • Metabolite function: • Lidocaine, aminopyrine • Clearance half life: • caffeine, BSP • indocyanine green (ICG) • Static • Cholestasis • Hep.cellular integrity • Synthesis • Liver perfusion: • CT, MRI

  16. Measurement of galactose elimination capacity (GEC) Principle: galactose phosphorylation by ATP in the liver, plotting of galactose serum concentrations in blood over time (4 h urine collection, blood sampling from min 20 to 45) Pathophysiological assumption: Elimination capacity reflects hepatocellular function and energetic status Clinical studies: decreased GEC in hepatitis, cirrhosis, liver donors, prognostication Methodological problems: galactose intolerance, cumbersome application Current applicability in current daily ICU practice: nihil

  17. Measurement of lidocaine conversion (MEGX test) Principle: hepatic conversion of lidocaine to MEGX by cytochrome system (CYP 3A/4A), determination of MEGX at time 0 and after 15 min after 1 mg/kg lidocaine Pathophysiological assumption: Reflects microsomal liver function, estimates functional liver reserve Clinical studies: prognostication in critically ill, pre + post-transplant liver function Methodological problems: interaction of cytochrome system with other medications affecting lidocaine conversion, need for special lab equipment Current applicability in current daily ICU practice: nihil

  18. Measurement of aminopyrine metabolism (antipyrine breath test) Principle: oral intake of radioactively labeled aminopyrine, demethylation + oxidation in the liver by cytochtome P-450 to antipyrine, measurement of exhaled 14CO2 Pathophysiological assumption: Reflects microsomal liver function, estimates functional liver reserve Clinical studies: prognostication in patients with chronic liver disease, studied in cardiac surgery patients and biliary obstruction Methodological problems: dependent on GI-motility, BMR, time consuming, special lab, radioactivity Current applicability in current daily ICU practice: nihil

  19. Measurement of caffeine metabolism or bromosulfophtalein (BSP) clearance Principle: - oral caffeine -> paraxanthine, theobromine, theophylline. Ratio metabolites/caffeine after 4, 8 and 12 h. Also described: caffeine breath test - iv BSP clearance at 30 and 45 min Pathophysiological assumption: Reflects microsomal liver function, estimates functional liver reserve Clinical studies: prognostication in patients with chronic liver disease or before liver resection Methodological problems: BSP: possibly fatal systemic reactions, special lab equipment Current applicability in current daily ICU practice: nihil

  20. Measurement of indocyanine green (ICG) plasma disappearance rate (PDR) PDR (%/min) • Water-soluble, fluorescent dye • binds to albumin + beta-lipoproteins • Selectively taken up by hepatocytes without ATP • Excreted unchanged in bile via ATP-dependent system • PDR = nl 18-25%/min, reflects: • sinusoidal perfusion • ICG uptake by hepatocytes • excretion into bile Sakka SG et al. Int Cre Med 2000

  21. PDR upon ICU admission = prognostic value comparable to APACHE II and SAPS • Good data in the setting of • Abdominal compartment syndrome • Complications after LTx • Morbidity after liver resection Kortgen A et al: Shock 2009 (n=48 with severe sepsis), Sakka SG 2007,

  22. Hypothesis: TIPSS, being a shunting procedure, can alter liver parenchymal perfusion, at least temporarily (n=15) HA = 25% flow 75% oxygenation PV = 75% flow 25% oxygenation

  23. Methods: Protocol Admission MICU PDR baseline TIPSS PDR 2 hr after TIPSS PDR 24 hr after TIPSS

  24. Results: PDR (%/min) before and after TIPSS

  25. Results: Change of PDR (%/min) from baseline

  26. Summary Techniques for monitoring of the GIT or liver function: usefulness for current ICU practice? • Measurement of splanchnic blood flow: DDUS yes but not really monitoring • Biomarkers of intestinal enterocyte mass or function: yes (potential) • ICG-PDR: yes, think green

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